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Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
Citation Impact (citeScore): 3
Number of Followers: 147  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3183 journals]
  • Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase
    • Abstract: Publication date: Available online 15 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Daniel J. Burkett, Brittney N. Wyatt, Mallory Mews, Anson Bautista, Ryan Engel, Chris Dockendorff, William A. Donaldson, Martin St. Maurice Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3’-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.Graphical abstractGraphical abstract for this article
  • Natural product-inspired profluorophores for imaging NQO1 activity in
           tumour tissues
    • Abstract: Publication date: Available online 15 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zhi M. Cheng, Wagner O. Valença, Gleiston G. Dias, Jamie Scott, Nicole D. Barth, Fabio de Moliner, Gabriela Souza, Richard J. Mellanby, Marc Vendrell, Eufrânio N. da Silva Júnior Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging.Graphical abstractGraphical abstract for this article
  • Biomimetic synthetic studies on meroterpenoids from the marine sponge Aka
           coralliphaga: Divergent total syntheses of siphonodictyal B, liphagal and
           corallidictyals A–D
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Kevin K.W. Kuan, Adrian W. Markwell-Heys, Michelle C. Cruickshank, Denise P. Tran, Robert M. Adlington, Jack E. Baldwin, Jonathan H. George The marine sponge Aka coralliphaga is a rich source of biologically active and structurally interesting meroterpenoids. Inspired by these natural products, we have used biosynthetic speculation to devise biomimetic syntheses of siphonodictyal B, liphagal and corallidictyals A–D from sclareolide. This work resulted in the development of new cascade reactions in the synthesis of liphagal, the reassignment of the structure of siphonodictyal B, and the realisation that corallidictyals A and B are possibly isolation artefacts.Graphical abstractGraphical abstract for this article
  • Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Miriam Girardini, Chiara Maniaci, Scott J. Hughes, Andrea Testa, Alessio Ciulli The von Hippel-Lindau (VHL) and cereblon (CRBN) proteins are substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. VHL and CRBN are also the two most popular E3 ligases being recruited by bifunctional Proteolysis-targeting chimeras (PROTACs) to induce ubiquitination and subsequent proteasomal degradation of a target protein. Using homo-PROTACs, VHL and CRBN have been independently dimerized to induce their own degradation. Here we report the design, synthesis and cellular activity of VHL-CRBN hetero-dimerizing PROTACs featuring diverse conjugation patterns. We found that the most active compound 14a induced potent, rapid and profound preferential degradation of CRBN over VHL in cancer cell lines. At lower concentrations, weaker degradation of VHL was instead observed. This work demonstrates proof of concept of designing PROTACs to hijack different E3 ligases against each other, and highlights a powerful and generalizable proximity-induced strategy to achieve E3 ligase knockdown.Graphical abstractGraphical abstract for this article
  • Sulfonate and sulfamate derivatives possessing benzofuran or
           benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors
    • Abstract: Publication date: Available online 13 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Seyed-Omar Zaraei, Mohammed I. El-Gamal, Zainab Shafique, Sayyeda Tayyeba Amjad, Saifullah Afridi, Sumera Zaib, Hanan S. Anbar, Randa El-Gamal, Jamshed Iqbal In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a-t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH2, NHMe, or NMe2) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC50 ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.Graphical abstractThe line representation (pink color) of active cavity of hCAXII, in complex with the selective and most potent inhibitor 1d shown in stick representationGraphical abstract for this article
  • Cyclic heptapeptides from the soil-derived fungus Clonostachys
    • Abstract: Publication date: Available online 12 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Nada M. Abdel-Wahab, Harwoko Harwoko, Werner E.G. Müller, Alexandra Hamacher, Matthias U. Kassack, Mostafa A. Fouad, Mohamed S. Kamel, Wenhan Lin, Weaam Ebrahim, Zhen Liu, Peter Proksch Three new cyclic heptapeptides (1–3) together with three known compounds (4–6) were isolated from a solid rice culture of the soil-derived fungus Clonostachys rosea. Fermentation of the fungus on white beans instead of rice afforded a new γ-lactam (7) and a known γ-lactone (8) that were not detected in the former extracts. The structures of the new compounds were elucidated on the basis of 1D and 2D NMR spectra as well as by HRESIMS data. Compounds 1 and 4 exhibited significant cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 4.1 and 0.1 µM, respectively. Compound 4 also displayed cytotoxicity against the A2780 human ovarian cancer cell line with an IC50 value of 3.5 µM. The preliminary structure-activity relationships are discussed.Graphical abstractGraphical abstract for this article
  • Natural Product Derived Promising Anti-MRSA Drug Leads: A Mini-Review
    • Abstract: Publication date: Available online 12 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Srikanth Gatadi, Jitendra Gour, Srinivas Nanduri Multi-drug resistant Staphylococcus aureus infections have created a critical need for the development of new classes of antibacterials. Discovery of new naturally derived antibacterial agents with new mechanism of action remains a high priority globally. Several of the available antibacterial agents like β-lactams, polyketides, phenylpropanoids, aminoglycosides, macrolides, glycopeptides, streptogramins and lipopeptides are natural products or their semisynthetic variations. In the current scenario of alarming rise in antibacterial resistance, revisiting natural products with modern chemistry and biology tools has fascinated many medicinal chemists for discovery and development of natural products or derived semisynthetic derivatives as effective antibacterial agents. This review underlines the structures and anti-MRSA activity of various natural product derivatives covering recent reports, in vivo activities and brief Structure Activity Relationships (SARs).Graphical abstractGraphical abstract for this article
  • Discovery of Fused Bicyclic Derivatives of 1H-Pyrrolo[1,2-c]imidazol-1-one
           as VDR Signaling Regulators
    • Abstract: Publication date: Available online 12 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Bin Xu, Mo-Yu Ding, Zhibing Weng, Zheng-Qing Li, Feng Li, Xia Sun, Qiu-Ling Chen, Yi-Tao Wang, Ying Wang, Guo-Chun Zhou The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-​pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also significantly downregulate p65 and upregulate p-p65 and ZD-3 is the most active one to NF-κB signaling, suggesting a possible induction of apoptosis through the regulation of NF-κB signal transduction mediated by VDR signaling. Compounds of ZD-3, ZD-4 and ZD-5 significantly counteract the interference by VDR shRNA, in which ZD-3 gets the highest compensation of VDR expression and the highest ratio of LC3-II/LC3-I, indicating that ZD-3 very likely activates VDR-mediated autophagy. Taken together, these 1H-pyrrolo[1,2-c]imidazol-​1-​one derivatives can modulate VDR signaling, possibly resulting in the regulation of some signal pathways to induce autophagy and apoptosis.Graphical abstractGraphical abstract for this article
  • Identification and Characterization of the First Fragment Hits for SETDB1
           Tudor Domain
    • Abstract: Publication date: Available online 12 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Pavel Mader, Rodrigo Mendoza-Sanchez, Aman Iqbal, Aiping Dong, Elena Dobrovetsky, Victoria B. Corless, Sean K. Liew, Scott R. Houliston, Renato Ferreira De Freitas, David Smil, Carlo C. Dela Sena, Steven Kennedy, Diego B. Diaz, Hong Wu, Ludmila Dombrovski, Abdellah Allali-Hassani, Jinrong Min, Matthieu Schapira, Masoud Vedadi, Peter J. Brown SET domain bifurcated protein 1 (SETDB1) is a human histone-lysine methyltransferase which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide binding groove of the Tandem Tudor Domain (TTD) of SETDB1. Herein, we describe the binding modes of these fragments and analogues and the biophysical characterization of key compounds. These confirmed small molecule fragments will inform the development of potent antagonists of SETDB1 interaction with histones.Graphical abstractGraphical abstract for this article
  • Xanthone, Benzophenone and Bianthrone Derivatives from the Hypersaline
           Lake-Derived Fungus Aspergillus wentii
    • Abstract: Publication date: Available online 11 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Imke C. Form, Michele Bonus, Holger Gohlke, Wenhan Lin, Georgios Daletos, Peter Proksch Five new metabolites, including the xanthone derivative wentixanthone A (1), the benzophenone wentiphenone A (2), the diastereomeric mixtures of the bianthrones wentibianthrone A (3a, b) and wentibianthrone B (4a, b), as well as (10R,10’S)-wentibianthrone C (5a) and (10R,10’R)-wentibianthrone C (5b) were obtained from the fungus Aspergillus wentii, isolated from soil of the hypersaline lake El Hamra in Wadi El-Natrun, Egypt. The structures of the isolated compounds were established by one and two-dimensional NMR and MS spectroscopic analysis. The relative configuration of bianthrones (3-5) was elucidated by comparison of experimental and computed 1H-NMR chemical shifts. Results of biological assays are reported.Graphical abstractGraphical abstract for this article
  • Microwave-assisted organic synthesis, structure–activity relationship,
           kinetics and molecular docking studies of non-cytotoxic benzamide
           derivatives as selective butyrylcholinesterase inhibitors
    • Abstract: Publication date: Available online 11 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sheeba Wajid, Asma Khatoon, Maria Aqeel Khan, Humaira Zafar, Shama Kanwal, Atta-ur-Rahman, M. Iqbal Choudhary, Fatima Z. Basha A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH3, -OC2H5, and -NO2) were synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure–activity relationship showed that the substitution of -Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1-12 were found to be non-cytotoxic, as compared with standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3-4, and 7-8 showed mixed mode of inhibition against BCHE, while compounds 2, 5-6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329 and many others.Graphical abstractGraphical abstract for this article
  • Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and
           antileishmanial activity
    • Abstract: Publication date: Available online 11 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Evanoel Crizanto de Lima, Frederico S. Castelo-Branco, Claudia C. Maquiaveli, André B. Farias, Magdalena N. Rennó, Nubia Boechat, Edson R. Silva Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with Ki in the range of 1.3–26 μM. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound 4 (EC50 of 12.7 ± 0.3 μM). In addition, in order to obtain further insight into the binding mode of such compounds, molecular docking studies were performed to obtain additional validation of experimental results. Considering these results, it is possible to conclude that α,α-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg.Graphical abstractGraphical abstract for this article
  • Upregulation of p53 through Induction of MDM2 degradation: Anthraquinone
    • Abstract: Publication date: Available online 11 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Alexander B. Draganov, Xiaoxiao Yang, Abiodun Anifowose, Ladie Kimberly C. De La Cruz, Chaofeng Dai, Nanting Ni, Weixuan Chen, Zeus De Los Santos, Lubing Gu, Muxiang Zhou, Binghe Wang In a previous study, a novel anthraquinone analog BW-AQ-101 was identified as a potent inducer of MDM2 degradation, leading to upregulation of p53 and apoptosis in cell culture studies. In animal models of acute lymphocytic leukemia, treatment with BW-AQ-101 led to complete disease remission. In this study, we systematically investigated the effect of substitution patterns of the core anthraquinone scaffold. Through cytotoxicity evaluation in two leukemia cell lines, the structure-activity relationship of thirty-two analogs has been examined. Several analogs with comparable or improved potency over BW-AQ-101 have been identified. Western-blot assays verified the effect of the potent compounds on the MDM2-p53 axis. The study also suggests new chemical space for further optimization work.Graphical abstractGraphical abstract for this article
  • The effects of Arctigenin-Valine ester on chemotherapy-induced
           myelosuppression in mice
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Mei Han, Xiaohuan Jia, Enbo Cai, Limin Yang, Min Dai, Nian Sun, Shan Jiang, Hui Shu ObjectiveTo explore whether Arctigenin-Valine ester (ARG-V) can treat myelosuppression caused by chemotherapy.MethodsThe number of peripheral blood cells of the mice was measured by an automatic blood analyzer, and the hematopoietic progenitor colonies CFU-GM, CFU-E, BFU-E, and CFU-Meg were cultured in vitro. Hematopoietic progenitor colonies and BMNCs were counted under an inverted microscope. The expressions of cytokines GM-CSF, EPO and TPO were detected by ELISA. The cell cycle was measured by flow cytometry. The expressions of related proteins MEK and p-ERK were quantitated by western blots, and the thymus index and spleen index were quantitated.ResultsAfter taking ARG-V, the peripheral blood cells of the mice gradually returned to normal, the number of nucleated cells in the bone marrow increased, the thymus index increased, the spleen index decreased, the number of hematopoietic progenitor cells increased, and the hematopoietic cytokines decreased. And ARG-V promoted the transformation of myelosuppression cells from G0/G1 to S and from S to G2/M. ARG-V could up-regulate the expression of MEK and p-ERK, and low dose ARG-V is not as effective in all aspects as high dose ARG-V.ConclusionARG-V can effectively alleviate the myelosuppression that caused by intraperitoneal injection of CTX in 100mg/kg, and ARG-V can promote the proliferation and differentiation of hematopoietic progenitor cells and improve immunity, and the effect of high-dose Arctigenin-Valine ester is more significant to some extent.Graphical abstractGraphical abstract for this article
  • Spirooxindole-pyrrolidine heterocyclic hybrids promotes apoptosis through
           activation of caspase-3
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Raju Suresh Kumar, Abdulrahman I. Almansour, Natarajan Arumugam, Faruq Mohammad, D. Kotresha, J. Carlos Menéndez A small library of spirooxindole-pyrrolidine hybrids have been synthesized for the first time in an ionic liquid, [bmim]Br in good to excellent yields employing a new class of non-stabilized azomethine ylides derived from isatin and tyrosine, a combination that has been rarely employed for the in situ generation of azomethine ylides using [3+2] cycloaddition strategy. Following the synthesis and characterization of the spirooxindole-pyrrolidine heterocyclic hybrids, they were tested for their anticancer activity as against the changes in the concentrations and time periods with different in vitro cell cultures containing cancer and non-cancer cells, where the results revealed for a potential therapeutic activity. Further analysis for the mechanism of cell death by the cancer cells indicated for the caspase-dependent apoptotic pathway, specifically mediated by caspase-3. Based on these results, it can be demonstrated that the synthesized spirooxindole-pyrrolidine hybrids may serve as one of the better therapeutic agents used for the treatment of malignant tumors.Graphical abstractGraphical abstract for this article
  • Tyrosinase inhibitory study of flavonolignans from the seeds of Silybum
           marianum (Milk thistle)
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Ji Yeong Kim, Jeong Yoon Kim, Janar Jenis, Zuo Peng Li, Yeong Jun Ban, Aizhamal Baiseitova, Ki Hun Park Anti-melanogenesis effects of silymarin from milk thistle have been reported recently, but detailed tyrosinase inhibition properties of individual components have not been investigated. This study purported to substantiate tyrosinase inhibition and its mechanism based on a single metabolite. The responsible components for tyrosinase inhibition of target source were found out as flavonolignans which consist of isosilybin A (1), isosilybin B (2), silydianin (3), 2,3-dihydrosilychristin (4), silychristin A (5), silychristin B (6) and silybin (7), respectively. The isolated flavonolignans (1–7) inhibited both monophenolase (IC50 = 1.7–7.6 µM) and diphenolase (IC50 = 12.1–44.9 µM) of tyrosinase significantly. Their inhibitions were 10-fold effective in comparison with their mother skeletons (8–10). Inhibitory functions were also proved by HPLC analysis using N-acetyl-l-tyrosine as substrate. The predominant formation of Emet·I was confirmed from a long prolongation of lag time and a decrease of the static state activity of the enzyme. All tested compounds had a significant binding affinity to tyrosinase with KSV values of 0.06–0.27 × 104 L·mol−1, which are well correlated with IC50s. In kinetic study, all flavonolignan (1–7) were mixed type I (KI 
  • Profiling withanolide A for therapeutic targets in neurodegenerative
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Erika A. Crane, Wolfgang Heydenreuter, Katharina R. Beck, Petra Strajhar, Jan Vomacka, Martin Smiesko, Elma Mons, Lydia Barth, Markus Neuburger, Angelo Vedani, Alex Odermatt, Stephan A. Sieber, Karl Gademann To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.Graphical abstractGraphical abstract for this article
  • Design and synthesis of a novel 1H-pyrrolo[3,2-b]pyridine-3-carboxamide
           derivative as an orally available ACC1 inhibitor
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Ryo Mizojiri, Noriyuki Nii, Moriteru Asano, Masako Sasaki, Yoshihiko Satoh, Yukiko Yamamoto, Hiroyuki Sumi, Hironobu Maezaki We initiated our structure-activity relationship (SAR) studies for novel ACC1 inhibitors from 1a as a lead compound. Our initial SAR studies of 1H-Pyrrolo[3,2-b]pyridine-3-carboxamide scaffold revealed the participation of HBD and HBA for ACC1 inhibitory potency and identified 1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1c as a potent ACC1 inhibitor. Although compound 1c had physicochemical and pharmacokinetic (PK) issues, we investigated the 1H-pyrrolo[3,2-b]pyridine core scaffold to address these issues. Accordingly, this led us to discover a novel 1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide derivative 1k as a promising ACC1 inhibitor, which showed potent ACC1 inhibition as well as sufficient cellular potency. Since compound 1k displayed favorable bioavailability in mouse cassette dosing PK study, we conducted in vivo Pharmacodynamics (PD) studies of this compound. Oral administration of 1k significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at a dose of 100 mg/kg. Accordingly, our novel series of potent ACC1 inhibitors represent useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases.Graphical abstractGraphical abstract for this article
  • Natural product–drug conjugates for modulation of TRPV1-expressing
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Charlotte Baker, Tiago Rodrigues, Bernardo P. de Almeida, Nuno L. Barbosa-Morais, Gonçalo J.L. Bernardes We report the design, synthesis and biological evaluation of natural product–drug conjugates for treatment of prostate cancers over-expressing the transient receptor potential vanilloid 1 (TRPV1) channel. We validate the relevance of TRPV1 as a target in prostate cancer patients by using a bioinformatics approach and provide proof-of-concept for the drug delivery strategy through bioorthogonal chemistry and stability assays under simulated physiological conditions. In cell-based assays, the constructs displayed modest activity. Moreover, we serendipitously discover that a stoichiometric combination of a TRPV1 agonist with a small, positively charged cytotoxic may provide new research avenues in personalized medicines for prostate cancer.Graphical abstractGraphical abstract for this article
  • Betulinic acid induces apoptosis and inhibits metastasis of human
           colorectal cancer cells in vitro and in vivo
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Anqi Zeng, Hua Hua, Li Liu, Junning Zhao Betulinic acid (BA) is a pentacyclic triterpenoids extracted from birch with a wide range of biological properties. Recent studies have shown that BA has significant cytotoxicity to various types of human cancer cells, and shows potential in cancer treatment. However, the efficacy of BA on human colorectal cancer tumor cells is still unclear. The purpose of our study was to evaluate the anti-cancer activity of BA in human colorectal cancer cells in vitro and in vivo to investigate the possible mechanism. In this experiment, we found that BA inhibited colorectal cancer cell lines in vitro with a time-dependent and dose-dependent manner. Moreover, BA could induce cell apoptosis by upregulating expression of Bax and cleaved caspase-3 and downregulating protein of Bcl-2. BA could increase the production of reactive oxygen species and reduce mitochondrial membrane potential of cancer cell, suggesting that BA induced cancer cells apoptosis by mitochondrial mediated pathways. Furthermore, BA significantly inhibited the migration and invasion of colorectal cancer cells, reduced the expression of matrix metalloproteinase (MMPs) and increased the expression of MMPs inhibitor (TIMP-2). In addition, the growth of tumor was significantly suppressed by intraperitoneal administration of 20 mg/kg/day of BA in a xenograft tumor mouse model of HCT-116. Histopathological and immunohistochemical analysis showed that MMP-2+ cells and Ki-67+ cells were reduced and cleaved caspase-3+ cells were increased in tumor tissues of mice after BA administration. The results showed that BA not only promoted the apoptosis of colorectal cancer cells, but also inhibited the metastasis of cancer cells. Our results suggest that BA can be a potential natural drug to inhibit the growth and metastasis of colorectal cancer.Graphical abstractGraphical abstract for this article
  • Optimization and Biological Evaluation of Nicotinamide Derivatives as
           Aurora Kinase Inhibitors
    • Abstract: Publication date: Available online 11 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Baohui Qi, Xingwei Xu, Ying Yang, Huan He, Xupeng Yue Aurora kinases are known to be overexpressed in various solid tumors and implicated in oncogenesis and tumor progression. A series of nicotinamide derivatives were synthesized and their biological activities were evaluated, including kinase inhibitory activity against Aur A and Aur B and in vitro antitumor activity against SW620, HT-29, NCI-H1975 and Hela cancer cell lines. In addition, the study of antiproliferation, cytotoxicity and apoptosis was performed meanwhile. As the most potent inhibitor of Aur A, 4-((3-bromo-4-fluorophenyl)amino)-6-chloro-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)nicotinamide (10l) showed excellent antitumor activity against SW620 and NCI-H1975 with IC50 values were 0.61 and 1.06 μM, while the IC50 values of reference compound were 3.37 and 6.67 μM, respectively. Furthermore, binding mode studies indicated that compound 10l forms better interaction with Aur A.Graphical abstractGraphical abstract for this article
  • Influence of nisin hinge-region variants on lantibiotic immunity and
           resistance proteins
    • Abstract: Publication date: Available online 10 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Julia Zaschke-Kriesche, Jens Reiners, Marcel Lagedroste, Sander H.J. Smits The rising existence of antimicrobial resistance, confirms the urgent need for new antimicrobial compounds. Lantibiotics are active in a low nanomolar range and represent good compound candidates. The lantibiotic nisin is well studied, thus it is a perfect origin for exploring novel lantibiotics via mutagenesis studies. However, some human pathogens like Streptococcus agalactiae COH1 already express resistance proteins against lantibiotics like nisin.This study presents three nisin variants with mutations in the hinge-region and determine their influence on both the growth inhibition as well as the pore-forming activity. Furthermore, we analyzed the effect of these mutants on the nisin immunity proteins NisI and NisFEG from Lactococcus lactis, as well as the nisin resistance proteins SaNSR and SaNsrFP from Streptococcus agalactiae COH1.We identified the nisin variant 20NMKIV24 with an extended hinge-region, to be an excellent candidate for further studies to eventually overcome the lantibiotic resistance in human pathogens, since these proteins do not recognize this variant well.Graphical abstractGraphical abstract for this article
  • l-amino+acid+moieties+for+the+treatment+of+HBV&rft.title=Bioorganic+&+Medicinal+Chemistry&rft.issn=0968-0896&">Synthesis, pharmacological evaluation, and mechanistic study of adefovir
           mixed phosphonate derivatives bearing cholic acid and l-amino acid
           moieties for the treatment of HBV
    • Abstract: Publication date: Available online 8 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Tao Li, Jing Li, Yang Yang, Yilin Han, Dirong Wu, Tao Xiao, Yang Wang, Ting Liu, Yonglong Zhao, Yongjun Li, Zeqin Dai, Xiaozhong Fu The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC50 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.Graphical abstractGraphical abstract for this article
  • Total Synthesis of Dryocrassin ABBA and its Analogues with Potential
           Inhibitory Activity against Drug-resistant Neuraminidases
    • Abstract: Publication date: Available online 8 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Bo Hou, Ze Liu, Xiao-Bei Yang, Wen-Fei Zhu, Jin-Yu Li, Liu Yang, Fu-Cai Reng, Yong-Feng Lv, Jiang-Miao Hu, Guo-Yang Liao, Jun Zhou The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6 %. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC50 values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.Graphical abstractTotal Synthesis of Dryocrassin ABBA and Analogue Structures with Potential Inhibitory Activity against Drug-resistant NeuraminidasesGraphical abstract for this article
  • Discovery of potent anti-inflammatory
           4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amines for use
           as Janus kinase inhibitors
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Yazhou Wang, Wei Huang, Minhang Xin, Pan Chen, Li Gui, Xinxin Zhao, Xinrong Zhu, Hongpeng Luo, Xin Cong, Jia Wang, Fei Liu The Janus kinase (JAK) family of tyrosine kinases has been proven to provide targeted immune modulation. Orally available JAK inhibitors have been used for the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Here, we report the design, synthesis and biological evaluation of 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amino derivatives as JAK inhibitors. Systematic structure–activity relationship studies led to the discovery of compound 7j, which strongly inhibited the four isoforms of JAK kinases. Molecular modeling rationalized the importance of cyanoacetyl and phenylmorpholine moieties. The in vivo investigation indicated that compound 7j possessed favorable pharmacokinetic properties and displayed slightly better anti-inflammatory efficacy than tofacitinib at the same dosage. Accordingly, compound 7j was advanced into preclinical development.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of
           3-hydroxyquinazoline-2,4(1H,3H)-diones as dual inhibitors of HIV-1 reverse
           transcriptase-associated RNase H and integrase
    • Abstract: Publication date: Available online 6 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ping Gao, Xiqiang Cheng, Lin Sun, Shu Song, Mar Álvarez, Joanna Luczkowiak, Christophe Pannecouque, Erik De Clercq, Luis Menéndez-Arias, Peng Zhan, Xinyong Liu A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.Graphical abstractGraphical abstract for this article
  • Synthesis, SAR study, and biological evaluation of novel
           2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as
           phosphodiesterase 10A inhibitors
    • Abstract: Publication date: Available online 6 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ayaka Chino, Shugo Honda, Masataka Morita, Koichi Yonezawa, Wataru Hamaguchi, Yasushi Amano, Hiroyuki Moriguchi, Mayako Yamazaki, Masaki Aota, Masaki Tomishima, Naoyuki Masuda Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.Graphical abstractGraphical abstract for this article
  • 2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: synthesis,
           evaluation of in vitro leishmanicidal activity, and mechanism of action
    • Abstract: Publication date: Available online 5 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zahra Mojallal-Tabatabaei, Parham Foroumadi, Mahsa Toolabi, Fereshteh Goli, Setareh Moghimi, Sussan Kaboudanian-Ardestani, Alireza Foroumadi The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4’-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.Graphical abstractGraphical abstract for this article
  • X-ray crystal structures, Density Functional Theory and docking on
           deacetylase enzyme for antiproliferative activity of hispolon derivatives
           on HCT116 colon cancer
    • Abstract: Publication date: Available online 5 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Miriam Rossi, Francesco Caruso, Ilaria Costanzini, Carmen Kloer, Aron Sulovari, Elena Monti, Marzia Gariboldi, Emanuela Marras, Neduri V. Balaji, Modukuri V. Ramani, Gottumukkala V. Subbaraju The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.Graphical abstractGraphical abstract for this article
  • Antitumor effect of chiral organotelluranes elicited in a murine melanoma
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Thaysa Paschoalin, Adam A. Martens, Álvaro T. Omori, Felipe V. Pereira, Luiz Juliano, Luiz R. Travassos, Glaucia M. Machado-Santelli, Rodrigo L.O.R. Cunha Protease roles in cancer progression have been demonstrated and their inhibitors display antitumor effects. Cathepsins are lysosomal cysteine proteases that have increased expression in tumor cells, and tellurium compounds were described as potent cysteine protease inhibitors and also assayed in several animal models. In this work, the two enantiomeric forms of 1-[Butyl(dichloro)-λ4-tellanyl]-2-[1S-methoxyethyl]benzene (organotelluranes RF-13R and RF-13S) were evaluated as inhibitors of cathepsins B and L, showing significant enantiodiscrimination. We observed their cytotoxic effects on a murine melanoma model, effectively inhibiting tumor progression in vivo. The enantiomers were able to inhibit melanoma cell viability, migration and invasion in vitro. Besides, RF-13S and RF-13R were able to inhibit endothelial cell angiogenesis using a tube formation assay in vitro, in a stereodependent manner. These organotelluranes affected cell morphology, showing disassembling of the actin cytoskeleton. These results suggest organotelluranes as potential antitumor agents, acting directly on tumor cell proliferation, migration and invasion, and on endothelial cells, disrupting angiogenesis, showing low toxicity and high efficiency. Taken together our results suggest that this class of compounds should be further studied to reveal their potential as antitumoral agents.Graphical abstractGraphical abstract for this article
  • Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)
    • Abstract: Publication date: Available online 5 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Erik de Heuvel, Abhimanyu K. Singh, Pierre Boronat, Albert J. Kooistra, Tiffany van der Meer, Payman Sadek, Antoni R. Blaazer, Nathan C. Shaner, Daphne S. Bindels, Guy Caljon, Louis Maes, Geert Jan Sterk, Marco Siderius, Michael Oberholzer, Iwan J.P. de Esch, David G. Brown, Rob Leurs Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.Graphical abstractGraphical abstract for this article
  • Thiazolidinedione and thiazole derivatives potentiate norfloxacin activity
           against NorA efflux pump over expression in Staphylococcus aureus 1199B
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Pedro Silvino Pereira, Maria do Carmo Alves de Lima, Pedro Paulo Marcelino Neto, Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Irwin Rose de Alencar Menezes, Jamerson Ferreira de Oliveira, Pascal Marchand, Henrique Douglas Melo Coutinho, Maria do Desterro Rodrigues, Teresinha Gonçalves da Silva Thiazol and thiazolidinedione derivatives are known in the literature for presenting several biological activities, such as anti-diabetic, anti-inflammatory, antiparasitic, antifungal and antimicrobial activity. With this in mind, this study reports on the synthesis and antibacterial activity of thiazole (NJ) and thiazolidinedione (NW) derivatives, as well as their effects in association with norfloxacin, against NorA efflux pumps in the Staphylococcus aureus 1199B (SA-1199B) strain. Among the 14 compounds evaluated, 9 were found to potentiate norfloxacin activity, with 4 compounds from the NJ series promoting a threefold norfloxacin MIC reduction. Molecular docking assays were used to confirm the binding mode of most active compounds. In the in silico study, the efficiency of the interaction of NJ series compounds with the NorA pump were evaluated. Derivatives from both series did not show considerable intrinsic antibacterial activity (MIC ˃ 1024 μg/mL) against any of the tested strains. However, the NJ16 and NJ17 compounds, when associated with norfloxacin, reduced the MIC of this drug threefold and inhibited NorA pumps in the 1199B strain. Moreover, some NW (05, 10, 18, 19 and 21) and NJ compounds (16, 17, 18 and 20) presented low to moderate cytotoxicity against normal cells. Molecular docking studies supported the potent in vitro inhibitory activity of NJ16 and NJ17, which showed NJ16 and NJ17 possessed more favorable binding energies of -9.03 Kcal/mol and -9.34 Kcal/mol, respectively. In addition, NJ16 showed different types of interactions involved in complex stabilization. In conclusion, NJ16 and NJ17, in combination with norfloxacin, were able to completely restore the antibacterial activity of norfloxacin against S. aureus SA-1199B, the norA-overexpressing strain, with low cytotoxicity in normal cells.Graphical abstractGraphical abstract for this article
  • Design, synthesis, biological evaluation of benzoyl amide derivatives
           containing nitrogen heterocyclic ring as potential VEGFR-2 inhibitors
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Fa-Qian Shen, Lu Shi, Ze-Feng Wang, Chen-Ru Wang, Jin-Jin Chen, Yi Liu, Han-Yue Qiu, Hai-Liang Zhu For the purpose of synthesizing drug candidates with desirable bioactivity, a class of benzoyl amide containing nitrogen heterocyclic ring derivatives targeting VEGFR-2 was designed and screened out using Discovery Studio. Eighteen target compounds were synthesized and then selected by some biological trials sequentially including inhibition of VEGFR-2, anti-proliferation in vitro, flow cytometry. Among them, compound 8h showed the best inhibitory activity (IC50 = 0.34 ±0.02 μM against VEGFR-2, IC50 = 1.08 ± 0.06 μM and 2.44 ± 0.15μM against MCF-7 and HepG-2, respectively, which were at the same inhibitory level with the commercially antitumor drug: vandetanib). In addition, flow cytometry demonstrated that compound 8h induced MCF-7 cell apoptosis through a cell membrane-mediated pathway. This research highlights the therapeutic potential of novel VEGFR-2 inhibitors in treating cancers and provides a promising strategy for drug discovery.Graphical abstractGraphical abstract for this article
  • Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Inverse Agonists
           of the CB1 Receptor – SAR Efforts Towards Selectivity and
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): George Amato, Robert Wiethe, Amruta Manke, Vineetha Vasukuttan, Rodney Snyder, Scott Runyon, Rangan Maitra Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 1 are explored to develop and test strategies for peripheralization. The piperidine of 1 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.Graphical abstractGraphical abstract for this article
  • Synthesis and Biological Evaluation of
           1-Alkylaminomethyl-1,1-Bisphosphonic Acids against Trypanosoma cruzi and
           Toxoplasma gondii
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Tamila Galaka, Bruno N. Falcone, Catherine Li, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21−33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47−49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54−56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.Graphical abstractGraphical abstract for this article
  • 5-Lipoxygenase as a drug target: A review on trends in inhibitors
           structural design, SAR and mechanism based approach
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shweta Sinha, Mukesh Doble, S.L. Manju The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and evaluation of novel N-(4-phenoxybenzyl)aniline
           derivatives targeting acetylcholinesterase, β-amyloid aggregation and
           oxidative stress to treat Alzheimer’s disease
    • Abstract: Publication date: Available online 4 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Pavan Srivastava, Prabhash Nath Tripathi, Piyoosh Sharma, Sushant Kumar Shrivastava Novel hybrids N-(4-phenoxybenzyl)aniline were designed, synthesized, and evaluated for their potential AChE inhibitory activity along with antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman’s method. Among all the compounds, 42 with trimethoxybenzene substituent showed maximum hAChE inhibition with the competitive type of enzyme inhibition (IC50 = 1.32 µM; Ki = 0.879 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability by most of the synthesized compounds. Meanwhile, compound 42 also inhibited AChE-induced Aβ aggregation (39.5–66.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 42. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 42 in brain homogenates.Graphical abstractGraphical abstract for this article
  • Development of Novel Lithocholic Acid Derivatives as Vitamin D Receptor
    • Abstract: Publication date: Available online 3 July 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hiroyuki Masuno, Yuko Kazui, Aya Tanatani, Shinya Fujii, Emiko Kawachi, Teikichi Ikura, Nobutoshi Ito, Keiko Yamamoto, Hiroyuki Kagechika Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and in vitro bioactivity evaluation of
           fluorine-containing analogues for sphingosine-1-phosphate 2 receptor
    • Abstract: Publication date: Available online 29 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zonghua Luo, Hui Liu, Robyn S. Klein, Zhude Tu Twenty eight new aryloxybenzene analogues were synthesized and their in vitro binding potencies toward S1PR2 were determined using a [32P]S1P competitive binding assay. Out of these new analogues, three compounds, 28c (IC50 = 29.9 ± 3.9 nM), 28e (IC50 = 14.6 ± 1.5 nM), and 28g (IC50 = 38.5 ± 6.3 nM) exhibited high binding potency toward S1PR2 and high selectivity over the other four receptor subtypes (S1PR1, 3, 4, and 5; IC50> 1000 nM). Each of the three potent compounds 28c, 28e, and 28g contains a fluorine atom that will allow developing F-18 labeled PET radiotracers for imaging S1PR2.Graphical abstractGraphical abstract for this article
  • Radiosynthesis and Evaluation of a Novel Monoacylglycerol Lipase
    • Abstract: Publication date: Available online 29 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Wakana Mori, Akiko Hatori, Yiding Zhang, Yusuke Kurihara, Tomoteru Yamasaki, Lin Xie, Katsushi Kumata, Kuan Hu, Masayuki Fujinaga, Ming-Rong Zhang Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2- arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[11C]carboxylate ([11C]6). Compound 6 exhibited high in vitro binding affinity (IC50 = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [11C]6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [11C]phosgene ([11C]COCl2), followed by a reaction with 3-(1-benzyl-1H-pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 ± 6.8% radiochemical yield (decay-corrected, n = 7) based on [11C]CO2 and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [11C]6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains.Graphical abstractGraphical abstract for this article
  • The Parmodulin NRD-21 is an Allosteric Inhibitor of PAR1 Gq Signaling with
           Improved Anti-Inflammatory Activity and Stability
    • Abstract: Publication date: Available online 29 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Disha M. Gandhi, Ricardo Rosas, Eric Greve, Kaitlin M. Kentala, N'Guessan D.-R. Diby, Vladyslava A. Snyder, Allison Stephans, Teresa H.W. Yeung, Saravanan Subramaniam, Elliot DiMilo, Khia E. Kurtenbach, Leggy A. Arnold, Hartmut Weiler, Chris Dockendorff Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.Graphical abstractGraphical abstract for this article
  • Synthesis of an amphiphilic tetrazine derivative and its application as a
           liposomal component to accelerate release of encapsulated drugs
    • Abstract: Publication date: Available online 29 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Kento Kannaka, Kohei Sano, Masayori Hagimori, Toshihide Yamasaki, Masayuki Munekane, Takahiro Mukai Tetrazine irreversibly reacts with dienophiles, and its derivatives find wide applications in the fields of biochemistry and biophysics. We have synthesized an amphiphilic tetrazine derivative (2-hexadecyl-N-(6-(6-(pyridin-2-yl)-1,2,4,5-tetrazine-3-yl)pyridin-3-yl)octadecanamide; 1), which has a hydrophilic tetrazine structure and hydrophobic alkyl chains. Liposomes composed of compound 1 and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) (PTz-liposome) were prepared. In search of a new drug delivery system (DDS), we investigated the viability of inverse electron-demand Diels-Alder, a reaction between tetrazine and 2-norbornene, on the surface of the liposomes to change membrane fluidity and promote spatial and temporal controlled release of the encapsulated drugs. Compound 1 was synthesized with a yield of 71%. MS analysis after incubation of 2-norbornene with PTz-liposome revealed the binding of 2-norbornene to tetrazine. Indium-111-labeled diethylenetriaminepentaacetic acid (111In-DTPA) was encapsulated inside PTz-liposome to evaluate the leakage of free 111In-DTPA from the liposomes quantitatively. After 24 h of adding 2-norbornene, the release percentage for PTz-liposome was significantly higher than that for the control liposome (without tetrazine structure). Furthermore, the membrane fluidity of the PTz-liposome was increased by adding 2-norbornene. These results suggested that the combination of dienophile and liposome containing a newly synthesized tetrazine derivative can be used as a controlled release DDS carrier.Graphical abstractGraphical abstract for this article
  • Introducing a New Category of Activity Cliffs with Chemical Modifications
           at Multiple Sites and Rationalizing Contributions of Individual
    • Abstract: Publication date: Available online 28 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Dagmar Stumpfe, Huabin Hu, Jürgen Bajorath Activity cliffs (ACs) are formed by structurally similar active compounds with large potency differences. In medicinal chemistry, ACs are of high interest because they reveal structure-activity relationship (SAR) information and SAR determinants. Herein, we introduce a new type of ACs that consist of analog pairs with different substitutions at multiple sites (multi-site ACs; msACs). A systematic search for msACs across different classes of bioactive compounds identified more than 4000 of such ACs, most of which had substitutions at two sites (dual-site ACs; dsACs). A hierarchical analog data structure was designed to analyze contributions of individual substitutions to AC formation. Single substitutions were frequently found to determine potency differences captured by dsACs. Hence, in such cases, there was redundancy of AC information. In instances where both substitutions made significant contributions to dsACs, additive, synergistic, and compensatory effects were observed. Taken together, the results of our analysis revealed the prevalence of single-site ACs (ssACs) in analog series, followed by dsACs, which reveal different ways in which paired substitutions contribute to the formation of ACs and modulate SARs.Graphical abstractGraphical abstract for this article
  • Biological Evaluation of Molecules of the azaBINOL Class as Antiviral
           Agents: Inhibition of HIV-1 RNase H Activity by
    • Abstract: Publication date: Available online 28 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ross D. Overacker, Somdev Banerjee, George F. Neuhaus, Selena Milicevic Sephton, Alexander Herrmann, James A. Strother, Ruth Brack-Werner, Paul R. Blakemore, Sandra Loesgen Inspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs and two BINOLs in a single-round infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOL B#24), which exhibited low-micromolar activity without associated cytotoxicity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). The in vitro studies indicated that azaBINOL B#24 acts on early stages of viral replication but before viral assembly and budding. Next we explored B#24’s activity against HIV-1 reverse transcriptase (RT) and individually tested for polymerase and RNase H activity. The azaBINOL B#24 inhibits RNase H activity and binds directly to the HIV-1 RT enzyme. Additionally, we observe additive inhibitory activity against pseudotyped viruses when B#24 is dosed in competition with the clinically used non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. When tested against a multi-drug resistant HIV-1 isolate with drug resistance associated mutations in regions encoding for HIV-1 RT and protease, B#24 only exhibits a 5.1-fold net decrease in IC50 value, while efavirenz’ activity decreases by 7.6-fold. These results indicate that azaBINOL B#24 is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.Graphical abstractGraphical abstract for this article
  • Melanogenic inhibitory effects of Triangularin in B16F0 melanoma cells, in
           vitro and molecular docking studies
    • Abstract: Publication date: Available online 27 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): María D. Santi, Mariana A. Peralta, Marcelo Puiatti, José Luis Cabrera, María G. Ortega The lack of secure therapies for hyperpigmentation disorders, without serious adverse effects, and the latest reports relating melanogenic disorders with development of neurodegenerative diseases, encourage the continuing search for new drugs for the treatment of such disorders. In this sense, the plant kingdom is an important source of bioactive natural products with great potential for the research and development of new therapeutics. The present study evaluated the anti-melanogenic activity of the natural methoxylated chalcone, 2’,6’-dihydroxy-4’-methoxy-3’-methylchalcone (Triangularin, T), on diphenolase activity from mushroom tyrosinase and on murine B16F0 melanoma cell model. In addition, molecular modelling studies were carried out in order to understand the inhibitory activity observed. T showed a potent anti-melanogenic activity being more active than kojic acid (KA) on tyrosinase isolated of both sources and on intracellular tyrosinase. Molecular docking studies displayed important interactions between T and the active site of tyrosinase. Our results suggest that T may be useful for the treatment of hyperpigmentary disorders.Graphical abstractGraphical abstract for this article
  • Anti-proliferative activity and structure-activity relationship of
           honokiol derivatives
    • Abstract: Publication date: Available online 27 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ding Lin, Zhongzhong Yan, Aiyu Chen, Jiao Ye, Aixi Hu, Juan Liu, Junmei Peng, Xiaoyun Wu As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC50 values of 5.04 and 7.08 μM respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.Graphical abstractGraphical abstract for this article
  • Green synthesis, biological evaluation, molecular docking studies and
           3D-QSAR analysis of novel phenylalanine linked
           quinazoline-4(3H)-one-sulphonamide hybrid entities distorting the malarial
           reductase activity in folate pathway
    • Abstract: Publication date: Available online 26 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Tarosh S. Patel, Jaimin D. Bhatt, Ritu B. Dixit, Chaitanya J. Chudasama, Bhavesh D. Patel, Bharat C. Dixit A modified Grimmel's method for N-heterocyclization of phenylalanine linked sulphonamide side arm at position-2 was optimized leading to 2,3-disustituted-4-quinazolin-(3H)-ones. Further, [Bmim][BF4]-H2O (IL) was used as green solvent as well as catalyst for the synthesis of twenty two hybrid quinazolinone motifs (4a-4v) by N-heterocyclization reaction using microwave irradiation technique. The in vitro screening of the hybrid entities against the malarial species Plasmodium falciparum yielded five potent molecules 4l, 4n, 4r, 4t & 4u owing comparable antimalarial activity to the reference drugs. In continuation, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure activity relationship. We also built a 3D-QSAR model to procure more information that could be applied to design new molecules with more potent Pf-DHFR inhibitory activity. The designed pharmacophore was recognized to be more potent for the selected molecules, exhibiting five pharmacophoric features. The active scaffolds were further evaluated for enzyme inhibition efficacy against alleged receptor Pf-DHFR computationally and in vitro, proving their candidature as lead dihydrofolate reductase inhibitors as well as the selectivity of the test candidates was ascertained by toxicity study against vero cells. The perception of good oral bioavailability was also proved by study of pharmacokinetic properties.Graphical abstractGraphical abstract for this article
  • 18F-Labeled Benzimidazopyridine Derivatives for PET Imaging of Tau
           Pathology in Alzheimer’s Disease
    • Abstract: Publication date: Available online 26 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sho Kaide, Hiroyuki Watanabe, Yoichi Shimizu, Haruka Tatsumi, Shimpei Iikuni, Yuji Nakamoto, Kaori Togashi, Masafumi Ihara, Hideo Saji, Masahiro Ono Hyperphosphorylated tau proteins are one of the neuropathological hallmarks in the Alzheimer’s disease (AD) brain. The in vivo imaging of tau aggregates with nuclear medical imaging probes is helpful for the further comprehension of and medical intervention in the AD pathology. For tau-selective PET imaging, we newly designed and synthesized 18F-labeled benzimidazopyridine (BIP) derivatives with fluoroalkylamino groups, [18F]IBIPF1 and [18F]IBIPF2, and evaluated their utilities as tau imaging probes. They both bound selectively to tau against amyloid β (Aβ) aggregates in AD brain sections in vitro, and showed good pharmacokinetics in mouse brains in vivo. Notably, [18F]IBIPF1 exhibited high tau-selectivity (Tau/Aβ ratio = 34.8), high brain uptake (6.22% ID/g at 2 min postinjection), and subsequent washout (2.77% ID/g at 30 min postinjection). In vivo analysis of radiometabolites indicated that [18F]IBIPF1 was stable against metabolism in the mouse brain. These encouraging preclinical results suggest that further structural optimization based on the BIP scaffold may lead to the development of more useful tau imaging probes.Graphical abstractGraphical abstract for this article
  • Design, Synthesis, Biological Activities, and Dynamic Simulation Study of
           Novel Thiourea Derivatives with Gibberellin Activity towards Arabidopsis
    • Abstract: Publication date: Available online 22 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zhikun Yang, Jine Wang, Hao Tian, Yan He, Hongxia Duan, Liusheng Duan, Weiming Tan Computer-aided drug design has advanced by leaps and bounds, and has been widely used in various fields, and especially in the field of drug discovery. Although the crystal structure of the gibberellin (GA) receptor GID1A had been reported in previous studies, there is still a lack of designs of gibberellin functional analogue based GID1A. In the present study, a series of 30 thiourea derivatives were designed, synthesized and biologically assayed. The results suggested that the synthetic compounds had good GA-like activities. Furthermore, the structure-activity relationship of the synthetic compounds was discussed, and the dynamic simulation and docking study revealed the binding properties of the GID1A receptor and compounds Y1, Y11, and Y21.Graphical abstractGraphical abstract for this article
  • Rational Approaches, Design Strategies, Structure Activity Relationship
           and Mechanistic Insights for Therapeutic Coumarin Hybrids
    • Abstract: Publication date: Available online 22 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Harbinder Singh, Jatinder Vir Singh, Kavita Bhagat, Harmandeep Kaur Gulati, Mohit Sanduja, Nitish Kumar, Nihar Kinarivala, Sahil Sharma Hybrid molecules, furnished by combining two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery that has attracted substantial traction in the past few years. Naturally occurring scaffolds such as coumarins display a wide spectrum of pharmacological activity including anticancer, antibiotic, antidiabetic and others, by acting on multiple targets. In this view, various coumarin-based hybrids possessing diverse medicinal attributes were synthesized in the last five years by conjugating coumarin moiety with other therapeutic pharmacophores. The current review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules. This review will be beneficial for medicinal chemist and chemical biologist, and in general to the drug discovery community and will facilitate the synthesis and development of novel, potent coumarin hybrid molecules serving as lead molecules for the treatment of complex disorders.Graphical abstractGraphical abstract for this article
  • Design, synthesis and molecular modelling of new bulky Fananserin
           derivatives with altered pharmacological profile as potential
    • Abstract: Publication date: Available online 21 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Przemysław Zaręba, Jolanta Jaśkowska, Izabela Czekaj, Grzegorz Satała It is now known that many neurotransmitter systems are responsible for diseases of the central nervous system (CNS). One of the most common CNS disease is depression. Considering that in the treatment and the genesis of depression, the most important are the serotonin receptors from 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 groups, and dopamine D2R this article describes searching for group of new ligands for mentioned receptors. In the searching for potentially useful compound, we decided to start from the structure of well-known Fananserin. We tried to developed new derivatives, with changed profile of activity compared to Fananserin. Literature analysis and virtual screening emerged group of halogenated long-chain arylpiperazines derivatives of 1,8 naphthosultam / lactam with hexyl carbon chain to synthesis. The compounds obtaining method was developed with a microwave assisted synthesis. Reactions were carried out in acetonitrile, water or in solvent-free conditions. The obtained compounds were tested for their affinity for the serotonin receptors mentioned above. The work managed to obtain compounds acting on selected serotonin receptors, including multifunctional 5-HT1A / 5-HT7 / D2 ligand 5k, dual 5-HT1A / D2 ligand 5j and selective 5-HT1A ligands 5r and 5c. The SAR analysis showed a visible dependence of affinity for the 5-HT6 receptors from structure of ligands. This relationship was discussed using molecular docking methods. A conformal analysis was also performed for selected ligands and the Fukui indexes were calculated using the DFT (B3LYP/6-311+G (d,p) level of theory) methods. The conducted research and analysis using molecular docking methods allows for selecting further pathways of structural modifications in the design of new ligands for serotonin receptors belonging to the group mentioned. What is more, conducted research show the potential using of Fukui indices to predict the biological activity of new molecules.Graphical abstractGraphical abstract for this article
  • Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based
           GluN2B receptor antagonists
    • Abstract: Publication date: Available online 20 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Marina Wagner, Dirk Schepmann, Simon M. Ametamey, Bernhard Wünsch Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [3H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 (Ki = 193 nM) bearing a p-fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ2 affinity (Ki = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ1 and σ2 receptors was rather low (Ki> 100 nM).Graphical abstractGraphical abstract for this article
  • Structure-activity relationship study of thiazolyl-hydroxamate derivatives
           as selective histone deacetylase 6 inhibitors
    • Abstract: Publication date: Available online 20 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gibeom Nam, Jun Min Jung, Hyun-Ju Park, Seung Yeop Baek, Ki Seon Baek, Hui yeon Mok, Da Eun Kim, Young Hoon Jung Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors.Graphical abstractGraphical abstract for this article
  • 2-Aryladenine derivatives as a potent scaffold for A1, A3 and dual A1/A3
           adenosine receptor antagonists: synthesis and structure-activity
    • Abstract: Publication date: Available online 20 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Filipe Areias, Carla Correia, Ashly Rocha, José Brea, Marián Castro, Maria I. Loza, M. Fernanda Proença, M. Alice Carvalho From a collection containing more than 1500 academic compounds, in silico screening identified a hit for the human A1 adenosine receptor containing a new purine scaffold. To study the structure activity relationships of this new chemical series for adenosine receptors, a library of 24 purines was synthesized and tested in radioligand binding assays at human A1, A2A, A2B and A3 adenosine receptor subtypes. Fourteen molecules showed potent antagonism at A1, A3 or dual A1/A3 adenosine receptors. This purine scaffold is an important source for novel biochemical tools and/or therapeutic drugs.Graphical abstractGraphical abstract for this article
  • Highly diverse cembranoids from the South China Sea soft coral Sinularia
           scabra as a new class of potential immunosuppressive agents
    • Abstract: Publication date: Available online 20 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Min Yang, Heng Li, Quan Zhang, Qi-Hao Wu, Geng Li, Kai-Xian Chen, Yue-Wei Guo, Wei Tang, Xu-Wen Li The first and in-depth chemical investigation of the South China Sea soft coral Sinularia scabra has resulted to the isolation of a library of diverse cembrane type diterpenoids, including six new compounds, namely xiguscabrates A and B (1 and 2), xiguscabral A (3), xiguscabrols A and B (4 and 5), and 8-epi-xiguscabrol B (6), and twenty-seven known analogs (7−33). Their structures were elucidated by extensive spectroscopic analysis and by the comparison with literature data. In bioassay, several isolates exhibited inhibitory effects on the ConA-induced T lymphocytes and/or LPS-induced B lymphocytes proliferation. Among them, compound 24 showed considerable specific inhibition on B cell proliferation, with IC50 value of 4.4 μM and selectivity index (SI) of 10.9. The structure-activity relationship (SAR) of the tested metabolites was analyzed, and the further mechanism study of the specific B-cell targeted immunosuppressive compound 24 on purified CD19+ B cells was also performed to uncover the effects on the function and maturity of B cells, including cytokines production, abnormal activation, antigen presenting capacity and plasma cells formation.Graphical abstractGraphical abstract for this article
  • Bypassing lantibiotic resistance by an effective nisin derivative
    • Abstract: Publication date: Available online 20 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Julia Zaschke-Kriesche, Lara V. Behrmann, Jens Reiners, Marcel Lagedroste, Yvonne Gröner, Rainer Kalscheuer, Sander H.J. Smits The need for new antibiotic compounds is rising and antimicrobial peptides are excellent candidates to fulfill this object. The bacteriocin subgroup lantibiotics, for example, are active in the nanomolar range and target the membranes of mainly Gram-positive bacteria. They bind to lipid II, inhibit cell growth and in some cases form pores within the bacterial membrane, inducing rapid cell death. Pharmaceutical usage of lantibiotics is however hampered by the presence of gene clusters in human pathogenic strains which, when expressed, confer resistance. The human pathogen Streptococcus agalactiae COH1, expresses several lantibiotic resistance proteins resulting in resistance against for example nisin.This study presents a highly potent, pore forming nisin variant as an alternative lantibiotic which bypasses the SaNSR protein. It is shown that this nisin derivate nisinC28P keeps its nanomolar antibacterial activity against L. lactis NZ9000 cells but is not recognized by the nisin resistance protein SaNSR.NisinC28P is cleaved by SaNSR in vitro with a highly decreased efficiency, as shown by an cleavage assay. Furthermore, we show that nisinC28P is still able to form pores in the membranes of L. lactis and is three times more efficient against SaNSR-expressing L. lactis cells than wildtype nisin.Graphical abstractGraphical abstract for this article
  • Novel meriolin derivatives as rapid apoptosis inducers
    • Abstract: Publication date: Available online 19 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Daniel Drießen, Fabian Stuhldreier, Annika Frank, Holger Stark, Sebastian Wesselborg, Björn Stork, Thomas J.J. Müller 3-(Hetero)aryl substituted 7-azaindoles possessing multikinase inhibitor activity are readily accessed in a one-pot Masuda borylation-Suzuki coupling sequence. Several promising derivatives were identified as apoptosis inducers and, emphasizing the multikinase inhibition potential, as sphingosine kinase 2 inhibitors. Our measurements provide additional insights into the structure-activity-relationship of meriolin derivatives, suggesting derivatives bearing a pyridine moiety with amino groups in 2-position as most active anticancer compounds and thus as highly promising candidates for future in vivo studies.Graphical abstractGraphical abstract for this article
  • Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly
           selective PDE10A inhibitor via core structure transformation from the
           stilbene moiety
    • Abstract: Publication date: Available online 19 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yuuki Koizumi, Yoshihito Tanaka, Takehiko Matsumura, Yoichi Kadoh, Haruko Miyoshi, Mitsuya Hongu, Kei Takedomi, Jun Kotera, Takashi Sasaki, Hiroyuki Taniguchi, Yumi Watanabe, Misae Takakuwa, Koki Kojima, Nobuyuki Baba, Itsuko Nakamura, Eiji Kawanishi We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.Graphical abstractGraphical abstract for this article
  • Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors
    • Abstract: Publication date: Available online 18 June 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Erik de Heuvel, Abhimanyu K. Singh, Ewald Edink, Tiffany van der Meer, Melanie van der Woude, Payman Sadek, Mikkel P. Krell-Jørgensen, Toine van den Bergh, Johan Veerman, Guy Caljon, Titilola D. Kalejaiye, Maikel Wijtmans, Louis Maes, Harry P. de Koning, Geert Jan Sterk, Marco Siderius, Iwan J.P. de Esch, David G. Brown, Rob Leurs Several 3’,5’-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.Graphical abstractGraphical abstract for this article
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    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s):
  • Identification of BMI1 promoter inhibitors from Streptomyces sp.
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi B-cell-specific Moloney murine leukemia virus region 1 (BMI1) is a central component of polycomb repressive complex 1 (PRC1), which maintains epigenetic repression of genes expression via chromatin condensation. BMI1 overexpression downregulates the expression of tumor suppressor genes, such as p16Ink4a and PTEN. BMI1 expression is upregulated in cancer stem cells (CSCs). Therefore, inhibitors of BMI1 expression have potential as therapeutic agents for cancer.This study aimed to identify BMI1 promoter inhibitors from actinomycetes. Using a recently constructed BMI1 promoter assay, we isolated three known compounds, elaiophylin (1), 2-methylelaiophylin (2), and nocardamin (3), from Streptomyces sp. IFM-11958 that inhibited BMI1 promoter activity with IC50 values of 30 nM, 447 nM, 22 µM, respectively. Elaiophylin (1) was the most potent. Western blot and PCR analyses revealed that elaiophylin (1) inhibited BMI1 expression at the mRNA level in human prostate cancer cells (DU145). Elaiophylin (1) also inhibited the sphere-forming activity of human hepatocellular carcinoma cells (Huh7), indicating that elaiophylin (1) suppresses the self-renewal capacity of CSCs. Elaiophylin (1) is the first BMI1 promoter inhibitor isolated from actinomycete metabolites.Graphical abstractGraphical abstract for this article
  • Enantioselective total synthesis of altersolanol A and N
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Bastian Mechsner, Dietrich Böse, Fabian Hogenkamp, Nadia Ledermann, Rudolf Hartmann, Kevin Bochinsky, Wolfgang Frey, Jörg Pietruszka The development of the first enantioselective total synthesis of altersolanol N is reported. The decisive step of the synthesis is the enantioselective formation of the tetrahydroanthraquinone nucleus by a [4 + 2]-cycloaddition in high yield and with excellent diastereo- and enantioselectivity (>95:5 dr and 95:5 er). In addition, a demanding selective monoacetylation of the OH group at the C-2 position was achieved: an epoxide ring opening with the participation of a neighbouring acetyl group could be established. The route proved to be an efficient alternative to also access enantiomerically pure altersolanol A.Graphical abstractGraphical abstract for this article
  • Correlating the structure and reactivity of a contact allergen, DNCB, and
           its analogs to sensitization potential
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Flora Kimani, Seong-Min Kim, Rachel Steinhardt, Aaron P. Esser-Kahn We report a study that seeks to find a correlation between the overall sensitization potential quantified by the expression of IL-8 by stimulated monocytes and the chemical structure of a model contact allergen, 2,4-dinitrochlorobenzene (DNCB). We show that structure and reactivity of the chemical compounds play an important role in activation of the monocytes and subsequent inflammation in tissue. However, we observed a non-linear correlation between the rate of reaction and biological activity indicating a required balance of stability and reactivity.Graphical abstractGraphical abstract for this article
  • Enhancing the ligand efficiency of anti-HIV compounds targeting
           frameshift-stimulating RNA
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Viktoriya S. Anokhina, John D. McAnany, Jessica H. Ciesla, Thomas A. Hilimire, Netty Santoso, Hongyu Miao, Benjamin L. Miller Ribosomal frameshifting, a process whereby a translating ribosome is diverted from one reading frame to another on a contiguous mRNA, is an important regulatory mechanism in biology and an opportunity for therapeutic intervention in several human diseases. In HIV, ribosomal frameshifting controls the ratio of Gag and Gag-Pol, two polyproteins critical to the HIV life cycle. We have previously reported compounds able to selectively bind an RNA stemloop within the Gag-Pol mRNA; these compounds alter the production of Gag-Pol in a manner consistent with increased frameshifting. Importantly, they also display antiretroviral activity in human T-cells. Here, we describe new compounds with significantly reduced molecular weight, but with substantially maintained affinity and anti-HIV activity. These results suggest that development of more “ligand efficient” enhancers of ribosomal frameshifting is an achievable goal.Graphical abstractGraphical abstract for this article
  • Design, synthesis and evaluation of antiproliferative activity of
           fluorinated betulinic acid
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Jizhen Li, Ling-Chu Chang, Kan-Yen Hsieh, Pei-Ling Hsu, Stephen J. Capuzzi, Ying-Chao Zhang, Kang-Po Li, Susan L. Morris-Natschke, Masuo Goto, Kuo-Hsiung Lee Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA’s pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.Graphical abstractGraphical abstract for this article
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    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s):
  • Discovery of a new autophagy inducer for A549 lung cancer cells
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Na Li, GuoJing Qu, JingNa Xue, Xiao Li, Xuan Zhao, YeHao Yan, DongFang Gao, Lu Zhang, Peng Wang, Ming Zhang, BaoXiang Zhao, JunYing Miao, ZhaoMin Lin Biological activities of a series of fluorescent compounds against human lung cancer cell line A549 were investigated. The results showed that (E)-1,3,3-trimethyl-2-(4-(piperidin-1-yl)styryl)-3H-indol-1-ium iodide (8) and (E)-2-(5,5-dimethyl-3-(4-(piperazin-1-yl)styryl)cyclohex-2-en-1-ylidene) malononitrile (11) could inhibit the growth of A549 cancer cells in a dose and time-dependent manner. Furthermore, compound 8 could trigger autophagy and apoptosis, but not obviously induce necrosis under the stimulatory condition. Therefore, 8 can be used as autophagy activator to investigate the regulatory mechanism of autophagy and may offer a new candidate for the treatment of lung cancer.Graphical abstractGraphical abstract for this article
  • Structure-based drug design of novel carborane-containing nicotinamide
           phosphoribosyltransferase inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Yasunobu Asawa, Kiyotaka Katsuragi, Akira Sato, Atsushi Yoshimori, Sei-ichi Tanuma, Hiroyuki Nakamura A series of carborane-containing NAMPT inhibitors were designed and synthesized based on the structure of compounds 1 and the NAMPT inhibitory activity was evaluated using NAMPT Colorimetric Assay. Among the compounds synthesized, compounds 2b and 2c showed significant NAMPT inhibitory activity with IC50 values of 0.098 ± 0.008 and 0.057 ± 0.001 µM, respectively. Docking simulation of compound 2 toward NAMPT using the crystal structure of the FK866-NAMPT complex (PDB code: 2GVJ) with replacing the boron atom type by the C3 atom type of carboranes predicted that the NAMPT inhibitory activity of 2c was improved by the hydrogen bond formation between the carborane amide and H191 of NAMPT. Although dicarborane compounds 38, 50, 51, and 55 were synthesize aiming to two hydrophobic pockets present in the binding pocket of NAMPT, their inhibitory activity was moderate.Graphical abstractGraphical abstract for this article
  • Synthetic glycopeptides reveal specific binding pattern and conformational
           change at O-mannosylated position of α-dystroglycan by POMGnT1 catalyzed
           GlcNAc modification
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Hiroshi Hinou, Seiya Kikuchi, Rika Ochi, Kota Igarashi, Wataru Takada, Shin-Ichiro Nishimura Structural and functional effects of core M1 type glycan modification catalyzed by protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) were investigated using a core M1 glycoform focused library of an α-dystroglycan fragment, 372TRGAIIQTPTLGPIQPTRV390. Evanescent-field fluorescence-assisted microarray system illuminated the specific binding pattern of plant lectins that can discriminate the glycan structure of core M1 glycan of the library. The comparative NMR analysis of synthetic glycopeptide having different length of the O-mannosylated glycans revealed a conformational change of the peptide backbone along with core M1 disaccharide formation. No long-range NOE signals of glycan-amino acid nor inter amino acid indicate the conformational change is induced by steric hindrance of core M1, the sole 1,2-O-modified form among protein binding sugar residue found in mammals.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of novel
           4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Xinzhou Bi, Jieming Li, Jiuhui Li, Wei Shi, Yuxuan Dai, Qifei Li, Wenjie Zhang, Wenlong Huang, Hai Qian, Cheng Jiang Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 μM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.Graphical abstractGraphical abstract for this article
  • Design, synthesis and evaluation of sulfonylurea-containing
           4-phenoxyquinolines as highly selective c-Met kinase inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Xiang Nan, Yi-Fan Jiang, Hui-Jing Li, Jun-Hu Wang, Yan-Chao Wu Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 µM, 0.064 µM, 0.16 µM and 0.49 µM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.Graphical abstractGraphical abstract for this article
  • Identification and immunological evaluation of novel TLR2 agonists through
           structure optimization of Pam3CSK4
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Xinming Du, Jiawen Qian, Yujie Wang, Mingming Zhang, Yiwei Chu, Yingxia Li Toll-like receptor 2 (TLR2) is a bridge between innate immunity and adaptive immunity. TLR2 agonists have been exploited as potential vaccine adjuvants and antitumor agents. However, no TLR2 agonists have been approved by FDA up to now. To discover drug-like TLR2 selective agonists, a novel series of Pam3CSK4 derivatives were designed based on the crystal structure of hTLR2-hTLR1-Pam3CSK4 complex, synthesized and evaluated for their immune-stimulatory activities. Among them, 35c was identified as a murine-specific TLR2 agonist, while 35f was a human-specific TLR2 agonist. Besides, 35d (human and murine TLR2 agonist) showed TLR2 agonistic activity comparable to Pam3CSK4, which included: elevated IL-6 expression level (EC50 = 83.08 ± 5.94 nM), up-regulated TNF-α and IL-6 mRNA expression and promoted maturation of DCs through activating the NF-κB signaling pathway. TLRs antibodies test showed that 35a and 35d were TLR2/1 agonists, while 35f was a TLR2/6 agonist.Graphical abstractGraphical abstract for this article
  • Design, synthesis and preliminary bioactivity studies of indomethacin
           derivatives as Bcl-2/Mcl-1 dual inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Chen Chen, Yiming Nie, Guangsen Xu, Xinying Yang, Hao Fang, Xuben Hou Bcl-2 family proteins, which divides into pro-apoptosis proteins and anti-apoptosis proteins, are involved in cell apoptosis progression. As numerous studies illustrated, targeting Bcl-2 family proteins is more and more attractive and practicable to cancer treatment. In this work, we designed and synthesized a series of indomethacin derivatives as new inhibitors for Bcl-2 family proteins. Our results of binding assay to Bcl-2 proteins, MTT assay and apoptotic assay indicated that some compounds had potent binding affinity to Bcl-2/Mcl-1 but not Bcl-XL. Furthermore, compound 8j showed improved anti-proliferative activity than known Bcl-2 inhibitor WL-276.Graphical abstractGraphical abstract for this article
  • Design, synthesis and biological evaluation of isochroman-4-one hybrids
           bearing piperazine moiety as antihypertensive agent candidates
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Shaowen Xie, Xinnan Li, Hao Yu, Pengfei Zhang, Jia Wang, Chaolei Wang, Shengtao Xu, Zheng Wu, Jie Liu, Zheying Zhu, Jinyi Xu 7,8-Dihydroxy-3-methyl-isochromanone-4 (XJP), is a polyphenolic natural product with moderate antihypertensive activity. To obtain new agents with stronger potency and safer profile, we employed XJP and naftopidil as the lead compounds to design and synthesize a novel class of hybrids as antihypertensive agent candidates. In the present study, a series of hybrids (6a–r) of XJP bearing arylpiperazine moiety, which is identified as the pharmacophore of naftopidil, were designed and synthesized as novel α1-adrenergic receptor antagonists. The biological evaluation showed that target compounds 6c, 6e, 6f, 6g, 6h, 6m and 6q possessed potent in vitro vasodilation potency and α1-adrenergic receptor antagonistic activity. Furthermore, the most potent compound 6e significantly reduced the systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs), which was comparable to that of naftopidil, and it had no observable effects on the basal heart rate, suggesting that 6e deserves to be further investigated as a potential clinical candidate for the treatment of hypertension.Graphical abstractGraphical abstract for this article
  • Application of the concept of oxime library screening by mass spectrometry
           (MS) binding assays to pyrrolidine-3-carboxylic acid derivatives as
           potential inhibitors of γ-aminobutyric acid transporter 1 (GAT1)
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Simone K. Huber, Georg Höfner, Klaus T. Wanner In the present study, the concept of oxime library screening by MS Binding Assays was successfully extended to N-substituted lipophilic pyrrolidine-3-carboxylic acid derivatives in the pursuit of varying the amino acid motif in order to identify new inhibitors for GAT1 and to broaden structure–activity-relationships for this target, the most abundant GABA transporter in the central nervous system. For the screening, 28 different oxime sub-libraries were employed that were generated by simple condensation reaction of an excess of pyrrolidine-3-carboxylic acid derivatives carrying a hydroxylamine functionality with various sub-libraries each assembled of eight aldehydes with broadly varying chemical structures and functionalities. The compounds responsible for the activity of an oxime sub-library were identified by deconvolution experiments performed by employing single oximes. Binding affinities of the oxime hits were confirmed in full-scale competitive MS Binding Assays. Thereby, oxime derivatives with a 1,1′-biphenyl moiety were found as the first inhibitors of mGAT1 comprising a pyrrolidine-3-carboxylic acid motif with affinities in the submicromolar range.Graphical abstractGraphical abstract for this article
  • Synthesis, biological evaluation, and molecular docking study of sulfonate
           derivatives as nucleotide pyrophosphatase/phosphodiesterase (NPP)
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Mohammad H. Semreen, Mohammed I. El-Gamal, Saif Ullah, Saquib Jalil, Sumera Zaib, Hanan S. Anbar, Joanna Lecka, Jean Sévigny, Jamshed Iqbal A new series of sulfonate derivatives 1a–zk were synthesized and evaluated as inhibitors of nucleotide pyrophosphatases. Most of the compounds exhibited good to moderate inhibition towards NPP1, NPP2, and NPP3 isozymes. Compound 1m was a potent and selective inhibitor of NPP1 with an IC50 value of 0.387 ± 0.007 µM. However, the most potent inhibitor of NPP3 was found as 1x with an IC50 value of 0.214 ± 0.012 µM. In addition, compound 1e was the most active inhibitor of NPP2 with an IC50 value of 0.659 ± 0.007 µM. Docking studies of the most potent compounds were carried out, and the computational results supported the in vitro results.Graphical abstractDocking pose of compound 1x into the crystal structure of NPP3.Graphical abstract for this article
  • Design, synthesis, and biological evaluation of some novel
           4-aminoquinazolines as Pan-PI3K inhibitors
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Huai-Wei Ding, Shu Wang, Xiao-Chun Qin, Jian Wang, Hong-Rui Song, Qing-Chun Zhao, Shao-Jiang Song A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents.Graphical abstractGraphical abstract for this article
  • Insights of synthetic analogues of anti-leprosy agents
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s): Smritilekha Bera, Dhananjoy Mondal Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leading cause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.Graphical abstractGraphical abstract for this article
  • Graphical abstract TOC
    • Abstract: Publication date: 1 July 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 13Author(s):
  • Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline
           heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and
           their molecular docking simulation
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Natarajan Arumugam, Abdulrahman I. Almansour, Raju Suresh Kumar, D. Kotresha, R. Saiswaroop, S. Venketesh A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-b]quinoxaline heterocyclic hybrids 7a–j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomethine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and l-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a–j were evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 7h and 7j displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC50 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.Graphical abstractGraphical abstract for this article
  • Synthesis of isochroman-4-ones and 2H-pyran-3(6H)-ones by gold-catalyzed
           oxidative cycloalkoxylation of alkynes
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Qing Zhao, Guilhem Henrion, Fabien Gagosz Gold catalysis is a convenient tool to oxidatively functionalize alkyne into a range of valuable compounds. In this article, we report a new access to isochroman-4-one and 2H-pyran-3(6H)-one derivatives that involves a gold-catalyzed oxidative cycloalkoxylation of an alkyne in the presence of a pyridine N-oxide. The reaction proceeds under mild conditions, is relatively efficient and exhibits a high functional group compatibility.Graphical abstractGraphical abstract for this article
  • Establishing cell painting in a smaller chemical biology lab – A
           report from the frontier
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Esben B. Svenningsen, Thomas B. Poulsen In this paper we will outline the efforts we have made recently to establish the profiling platform known as cell painting in our laboratory. This platform, which is based on fluorescence microscopy, allows rapid and cheap access to bioactivity fingerprints for small molecules and thereby can contribute with important information in many experimental situations that is faced in laboratories involved in molecular probe design, mode-of-action studies or that perform focused phenotypic screens. We have tried to achieve the following two objectives: (1) provide a detailed description of the hurdles that we had to overcome during establishment and describe our final protocol; (2) provide a more pedagogical description of the different methods used to analyse and represent data from this experiment. Finally, we provide an example of how the method can be used to clarify mechanistic dichotomies.Graphical abstractGraphical abstract for this article
  • Synthesis, characterization, and photodynamic therapy activity of
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Zhao Zhang, Hua-Jun Yu, Shang Wu, Hui Huang, Li-Ping Si, Hai-Yang Liu, Lei Shi, Hai-Tao Zhang Water-soluble porphyrins are considered promising drug candidates for photodynamic therapy (PDT). This study investigated the PDT activity of a new water-soluble, anionic porphyrin (1-Zn), which possesses four negative charges. The photodynamic anticancer activity of 1-Zn was investigated by the MTT assay, with mTHPC as a positive control. The cellular distribution was determined by fluorescence microscopy. Holographic and phase contrast images were recorded after 1-Zn treatment with a HoloMonitor™ M3 instrument. The inhibition of A549 cell growth achieved by inducing apoptosis was investigated by flow cytometry and fluorescence microscopy. DNA damage was investigated by the comet assay. The expression of apoptosis-related proteins was also measured by western blot assays. 1-Zn had better phototoxicity against A549 cells than HeLa and HepG2 cancer cells. Interestingly, 1-Zn was clearly located almost entirely in the cell cytoplasmic region/organelles. The late apoptotic population was less than 1.0% at baseline in the untreated and only light-treated cells and increased to 40.5% after 1-Zn treatment and irradiation (P 
  • Purification, structural elucidation, antioxidant capacity and
           neuroprotective potential of the main polyphenolic compounds contained in
           Achyrocline satureioides (Lam) D.C. (Compositae)
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Marcela Martínez-Busi, Florencia Arredondo, David González, Carolina Echeverry, Mauricio A. Vega-Teijido, Diego Carvalho, Alejandra Rodríguez-Haralambides, Felicia Rivera, Federico Dajas, Juan A. Abin-Carriquiry Achyrocline satureioides (Lam) D.C (Compositae) is a native medicinal plant of South America traditionally utilized for its anti-inflammatory, sedative and anti-atherosclerotic properties among others. Neuroprotective effects have been reported in vivo and could be associated to its elevated content of flavonoid aglycones. In the present study we performed the isolation and structure elucidation of the major individual flavonoids of A. satureioides along with the in vitro characterization of their individual antioxidant and neuroprotective properties in order to see their putative relevance for treating neurodegeneration.Exact mass, HPLC-MS/MS and 1H NMR identified dicaffeoyl quinic acid isomers, quercetin, luteolin, isoquercitrin, and 3-O-methylquercetin as the mayor polyphenols. Flavonoids intrinsic redox properties were evaluated in the presence of the endogenous antioxidants GSH and Ascorbate. Density Functional Theory (DFT) molecular modeling and electron density studies showed a theoretical basis for their different redox properties. Finally, in vitro neuroprotective effect of each isolated flavonoid was evaluated against hydrogen peroxide-induced toxicity in a primary neuronal culture paradigm. Our results showed that quercetin was more efficacious than luteolin and isoquercitrin, while 3-O-methylquercetin was unable to afford neuroprotection significantly. This was in accordance with the susceptibility of each flavonoid to be oxidized and to react with GSH. Overall our results shed light on chemical and molecular mechanisms underlying bioactive actions of A. satureioides main flavonoids that could contribute to its neuroprotective effects and support the positive association between the consumption of A. satureioides as a natural dietary source of polyphenols, and beneficial health effect.Graphical abstractGraphical abstract for this article
  • Design, synthesis, fungicidal activity and molecular docking studies of
           novel 2-((2-hydroxyphenyl)methylamino)acetamide derivatives
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Zilong Tang, Xinxing Li, Yuan Yao, Yongcun Qi, Ming Wang, Ningning Dai, Yuhao Wen, Yichao Wan, Lifen Peng A series of novel 2-hydroxyphenyl substituted aminoacetamides was designed by molecular hybridization of the aminoacetamide scaffold and 2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal activities were evaluated. Some of the target compounds showed excellent antifungal activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e displayed the most potent activity against S. sclerotiorum with EC50 = 2.89 µg/mL, which was lower than that of commercial chlorothalonil. The systematic studies provided strong confidence that the hydroxyl group and the carbonyl group are crucial for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could be one of the potential action targets of our compounds.Graphical abstractGraphical abstract for this article
  • In silico study of M18 aspartyl amino peptidase (M18AAP) of Plasmodium
           vivax as an antimalarial drug target
    • Abstract: Publication date: 15 June 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 12Author(s): Subhashree Rout, Rajani Kanta Mahapatra Plasmodium vivax (Pv) is the second most malaria causing pathogen among Plasmodium species. M18 aspartic aminopeptidase (M18AAP) protein is a single gene copy present in Plasmodium. This protein is functional at the terminal stage of hemoglobin degradation of host and completes the hydrolysis process which makes it an important target for new chemotherapeutics. No experimental and structural study on M18AAP protein of P. vivax is reported till today. This paper advocates the application of multiple computational approaches like protein model prediction, ligand-based 3D QSAR study, pharmacophore, structure-based virtual screening and molecular docking simulation for identification of potent lead molecules against the enzyme. The 3D QSAR model was developed using known bioactive compounds against the PvM18AAP protein which statistically signify the k-NN model with q^2 = 0.7654. The study reports a lead molecule from ligand-centric approach with good binding affinity and possessing lowest docking score. The findings will be helpful for in-vivo and in-vitro validations and development of potent anti-malarial molecules against the drug resistant strains of malaria parasite.Graphical abstractGraphical abstract for this article
  • Development of covalent antagonists for β1- and β2-adrenergic
    • Abstract: Publication date: Available online 24 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Tobias Schwalbe, Harald Hübner, Peter Gmeiner The selective covalent tethering of ligands to a specific GPCR binding site has attracted considerable interest in structural biology, molecular pharmacology and drug design. We recently reported on a covalently binding noradrenaline analog (FAUC37) facilitating crystallization of the β2-adrenergic receptor (β2ARH2.64C) in an active state. We herein present the stereospecific synthesis of covalently binding disulfide ligands based on the pharmacophores of adrenergic β1- and β2 receptor antagonists. Radioligand depletion experiments revealed that the disulfide-functionalized ligands were able to rapidly form a covalent bond with a specific cysteine residue of the receptor mutants β1ARI2.64C and β2ARH2.64C. The propranolol derivative (S)-1a induced nearly complete irreversible blockage of the β2ARH2.64C within 30 minutes incubation. The CGP20712A-based ligand (S)-4 showed efficient covalent blocking of the β2ARH2.64C at very low concentrations. The analog (S)-5a revealed extraordinary covalent cross-linking at the β1ARI2.64C and β2ARH2.64C mutant while retaining a 41-fold selectivity for the β1AR wild type over β2AR. These compounds may serve as valuable molecular tools for studying β1/β2 subtype selectivity or investigations on GPCR trafficking and dimerization.Graphical abstractGraphical abstract for this article
  • A novel indirubin derivative that increases somatic cell plasticity and
           inhibits tumorigenicity
    • Abstract: Publication date: Available online 20 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Woong-Hee Kim, Pyeonghwa Jeong, Seon-Wook Kim, Haaglim Cho, Jeong-min Lee, Shinae Seo, Haihong Shen, Youngkeun Ahn, Da-Woon Jung, Yong-Chul Kim, Darren R. Williams Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z,3E)-5-hydroxy-5'-nitro-2'-oxo-[2,3'-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases.Graphical abstractGraphical abstract for this article
  • Investigation of Flexibility of Neuraminidase 150-loop using Tamiflu
           Derivatives in Influenza A Viruses H1N1
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Václav Zima, Carlos Berenguer Albiñana, Kateřina Rojíková, Jana Pokorná, Petr Pachl, Pavlína Řezáčová, Jason Hudlicky, Václav Navrátil, Pavel Majer, Jan Konvalinka, Milan Kožíšek, Aleš Machara This study focuses on design, synthesis and in vitro evaluation of inhibitory potency of two series of sialylmimetic that target an exosite (“150-cavity”) adjacent to the active site of influenza neuraminidases from A/California/07/2009 (H1N1) pandemic strain and A/chicken/Nakorn-Patom/Thailand/CU-K2-2004 (H5N1). The structure-activity analysis as well as 3-D structure of the complex of parental compound with the pandemic neuraminidase p09N1 revealed high flexibility of the 150-cavity towards various modification of the neuraminidase inhibitors. Furthermore, our comparison of two methods for inhibition constant determination performed at slightly different pH values suggest that the experimental conditions of the measurement could dramatically influence the outcome of the analysis in the compound-dependent manner. Therefore, previously reported Ki values determined at non-physiological pH should be carefully scrutinized.Graphical abstractGraphical abstract for this article
  • 2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sungjin Ahn, Jungmin Kim, Seungchan An, Jeong Joo Pyo, Daram Jung, Joochang Lee, Seok Young Hwang, Junpyo Gong, Iljin Shin, Hong Pyo Kim, Hyoungsu Kim, Minsoo Noh Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases.Graphical abstractGraphical abstract for this article
  • Design, synthesis, and biological evaluation of novel
           4-oxobenzo[d]1,2,3-triazin-benzylpyridinum derivatives as potent
           anti-Alzheimer agents
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Fahimeh Hosseini, Ali Ramazani, Maryam Mohammadi-Khanaposhtani, Maliheh Barazandeh Tehrani, Hamid Nadri, Bagher Larijani, Mohammad Mahdavi Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a-q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H2O2-induced PC12 oxidative stress, but low activity against β-secretase.Graphical abstractGraphical abstract for this article
  • Synthesis of Distal and Proximal fleximer Base Analogues and Evaluation in
           the Nucleocapsid Protein of HIV-1
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Therese Ku, Natalie Lopresti, Matthew Shirley, Mattia Mori, Jan Marchant, Xiao Heng, Maurizio Botta, Michael Summers, Katherine Seley-Radtke Anti-HIV-1 drug design has been notably challenging due to the virus’ ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.Graphical abstractGraphical abstract for this article
  • Capsaicin-like analogue induced selective apoptosis in A2058 melanoma
           cells: Design, synthesis and molecular modeling
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gustavo José Vasco Pereira, Maurício Temotheo Tavares, Ricardo Alexandre Azevedo, Barbara Behr Martins, Micael Rodrigues Cunha, Rajesh Bhardwaj, Yara Cury, Vanessa Olzon Zambelli, Euzébio Guimarães Barbosa, Matthias A. Hediger, Roberto Parise-Filho The use of molecules inspired by natural scaffolds has proven to be a very promising and efficient method of drug discovery. In this work, capsaicin, a natural product from Capsicum peppers with antitumor properties, was used as a prototype to obtain urea and thiourea analogues. Among the most promising compounds, the thiourea compound 6g exhibited significant cytotoxic activity against human melanoma A2058 cells that was twice as high as that of capsaicin. Compound 6g induced significant and dose-dependent G0/G1 cell cycle arrest in A2058 cells triggering cell death by apoptosis. Our results suggest that 6g modulates the RAF/MEK/ERK pathway, inducing important morphological changes, such as formation of apoptotic bodies and increased levels of cleaved caspase-3. Compared to capsaicin, 6g had no significant TRPV1/6 agonist effect either irritant effects on mice. Molecular modeling studies corroborate the biological findings and suggest that 6g, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. Inverse virtual screening strategy found MEK1 as a possible biological target for 6g. Consistent with these findings, our observations suggested that 6g could be developed as a potential anticancer agent.Graphical abstractGraphical abstract for this article
  • Optimization of Novel Reversible Bruton’s Tyrosine Kinase Inhibitors
           Identified Using Tethering-Fragment-Based Screens
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Brian T. Hopkins, Eris Bame, Noah Bell, Tonika Bohnert, Jon K. Bowden-Verhoek, Minna Bui, Mark T. Cancilla, Patrick Conlon, Patrick Cullen, Daniel A. Erlanson, Junfa Fan, Tarra Fuchs-Knotts, Stig Hansen, Stacey Heumann, Tracy J. Jenkins, Douglas Marcotte, Bob McDowell, Elisabeth Mertsching, Ella Negrou, Kevin L. Otipoby Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton’s tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.Graphical abstractGraphical abstract for this article
  • Development of Novel Macrocyclic Small Molecules that Target CTG
           Trinucleotide Repeats
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Julio F. Serrano, JuYeon Lee, L. Daniel Curet, Lauren D. Hagler, Sarah E. Bonson, Emma J. Schuster, Steven C. Zimmerman We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to dCTG mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions and form a 1:1 complex. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.Graphical abstractGraphical abstract for this article
  • Highly tunable thiosulfonates as a novel class of cysteine protease
           inhibitors with anti-parasitic activity against Schistosoma mansoni
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): D.J. Ward, H. Van de Langemheen, E. Koehne, A. Kreidenweiss, R.M.J. Liskamp The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27 - 30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds.Graphical abstractGraphical abstract for this article
  • Eicosanoid Mediation of Cannabinoid Actions
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sumner H. Burstein Interactions between cannabinoids and eicosanoids have been observed for the last several decades and account for a variety of cannabinoid actions. These were seen both in vitro and in vivo and may provide a molecular basis for these actions. Some of the topics included in this review are; effects on adenylate cyclase activity, alteration of behavioral responses, reduction of pain sensation, reduction and resolution of inflammation, hypotensive and vasorelaxant responses, anti-cancer and anti-metastatic activities, reduction of intraocular pressure and others. The most widely studied cannabinoids so far are tetrahydrocannabinol and cannabidiol. However, synthetic agents such as CP55,940, ajulemic acid, JWH-133 and WIN-55,212-2 were also investigated for interaction with eicosanoids. The endocannabinoids anandamide and 2-arachidonoylglycerol have been examined as well. Among the eicosanoids mediating cannabinoid actions are PGE2, 15-deoxy- Δ 12, 14-prostaglandin-J2 , lipoxin A4, lipoxin B4, and leukotriene B4. Enzyme activities involved include monoacylglycerylipase, adenylatecyclase, phospholipase A2, cyclooxygenases-1, 2 and 5, lipoxygenases-12 and 15. Receptors involved include CB1, CB2 and the EP3 and EP3 prostanoid receptors. While not all cannabinoid activities can be accounted for, many are best explained by eicosanoid participation. The recent surge in interest in “medical marijuana” makes understanding mechanisms of cannabinoid actions particularly important.Graphical abstractGraphical abstract for this article
  • New analogs of SYA013 as sigma-2 ligands with anticancer activity
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gladys Asong, Xue Y Zhu, Barbara Bricker, Terrick Andey, Felix Amissah, Nazarius Lamango, Seth Y Ablordeppey Our previous study has revealed 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one·2HCl (SYA013) 1 as a sigma ligand with moderate selectivity for the sigma-2 receptor. Given the overexpression of sigma receptors in solid tumors and reports of sigma ligands with anticancer activities, we selected 1 for evaluation in several solid tumor cell lines. In addition, we have synthesized new analogs of 1 and now report that several of them bind preferentially at the sigma-2 receptor and have shown inhibition of several cancer cell lines including MDA-MB-231, MDA-MB-486, A549, PC-3, MIA PaCa-2 and Panc-1 cells. In particular, compounds 1 and 12 have demonstrated sub-micromolar activity against the Panc-1 cell line. It has also been observed that several of these compounds demonstrate selective toxicity toward cancer cells, when compared to normal cells.Graphical abstractGraphical abstract for this article
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