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Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
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  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3157 journals]
  • Development of an anti-hepatitis B virus (HBV) agent through the
           structure-activity relationship of the interferon-like small compound
           CDM-3008
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Nobuaki Takahashi, Kyohei Hayashi, Yusuke Nakagawa, Yutaka Furutani, Mariko Toguchi, Yumi Shiozaki-Sato, Masayuki Sudoh, Soichi Kojima, Hideaki Kakeya Hepatitis B, a viral infectious disease caused by hepatitis B virus (HBV), is a life-threatening disease that leads liver cirrhosis and liver cancer. Because the current treatments for HBV, such as an interferon (IFN) formulation or nucleoside/nucleotide analogues, are not sufficient, the development of a more effective agent for HBV is urgent required.CDM-3008 (1, 2-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-a][1,8]naphthyridine scaffold that shows anti-HCV activity with an IFN-like effect. Here, we report that 1 was also effective for HBV, although the solubility and metabolic stability were insufficient for clinical use. Through the structure-activity relationship (SAR), we discovered that CDM-3032 (11, N-(piperidine-4-yl)-2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxamide hydrochloride) was more soluble than 1 (>30 mg/mL for 11 versus 0.92 mg/mL for 1). In addition, the half-life period of 11 was dramatically improved in both mouse and human hepatic microsomes (T1/2,>120 min versus 58.2 min in mouse, and>120 min versus 34.1 min in human, for 11 and 1, respectively).Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s):
       
  • Corrigendum to “Structure-activity studies of a macrocyclic peptide
           inhibitor of histone lysine demethylase 4A” [Bioorg. Med. Chem. 26/6
           (2018) 1225–1231]
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Toby Passioura, Bhaskar Bhushan, Anthony Tumber, Akane Kawamura, Hiroaki Suga
       
  • The association between anti-tumor potency and structure-activity of
           protein-kinases inhibitors based on quinazoline molecular skeleton
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Yang Li, Jie Xiao, Qizhi Zhang, Wenmei Yu, Mengqin Liu, Yu Guo, Jun He, Yunmei Liu Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives. Thus, several studies have been approved for the use of quinazoline derivatives as inhibitors of other kinases, including Src and histone deacetylase. The aim of the present review was to summarize the mechanism of quinazoline compounds as PK inhibitors, their biological structure-activity relationship such as the substituted quinazoline compounds with different functional groups in the apoptotic process, and their effect on the proliferation of tumor cells. The development of novel agents based on the antitumor functions of quinazoline molecular compounds may improve the clinical outcomes of the affected population, particularly in patients with cancer.Graphical abstractGraphical abstract for this article
       
  • Harzianoic acids A and B, new natural scaffolds with inhibitory effects
           against hepatitis C virus
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Bo Li, Li Li, Zonggen Peng, Dong Liu, Longlong Si, Jing Wang, Bochuan Yuan, Jian Huang, Peter Proksch, Wenhan Lin Two new sesquiterpene-based analogues, namely harzianoic acids A (1) and B (2), were isolated from a sponge-associated fungus Trichoderma harzianum. Their structures were determined on the basis of the extensive spectroscopic analyses in association with the ECD data for the configurational assignment. Harzianoic acids A and B were structurally characterized as a sesquiterpene and a norsesquiterpene with a cyclobutane nucleus, which is uncommonly found from nature. Both compounds exhibited the inhibitory activity to reduce the HCV RNA levels with low cytotoxicity. The preliminary investigation of the mode of action revealed that the compounds blocked the entry step in the HCV life cycle, while the viral E1/E2 and the host cell CD81 were the potential target proteins.Graphical abstractGraphical abstract for this article
       
  • Tuning the selectivity of N-alkylated styrylquinolinium dyes for sensing
           of G-quadruplex DNA
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Ming-Qi Wang, Jing Xu, Lan Zhang, Yue Liao, Heng Wei, Ying-Ying Yin, Qiang Liu, Yuan Zhang Selective and sensitive detection of G-quadruplex DNA structures is an important issue and attracts extensive interest. To this end, numerous small molecular fluorescent probes have been designed. Here, we present a series of N-alkylated styrylquinolinium dyes named Ls-1, Ls-2 and Ls-3 with varying side groups at the chain end. We found that these dyes exhibited different binding behaviors to DNAs, and Ls-2 with a sulfonato group at the chain end displayed sensitivity and selectivity to G-quadruplex DNA structures in vitro. The characteristics of this dye and its interaction with G-quadruplex DNA were comprehensively investigated by means of UV–vis spectrophotometry, fluorescence, circular dichroism and molecular docking. Furthermore, confocal fluorescence images and MTT assays indicated dye Ls-2 could pass through membrane and enter the living HepG2 cells with low cytotoxicity.Graphical abstractGraphical abstract for this article
       
  • Synthesis and preliminary evaluation of 18F-icotinib for EGFR-targeted PET
           imaging of lung cancer
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Xinmiao Lu, Cheng Wang, Xiao Li, Peilin Gu, Lina Jia, Lan Zhang Epidermal growth factor receptor (EGFR) has emerged as an attracting target in the field of imaging and treatment for non-small cell lung cancer (NSCLC). Radiolabeled EGFR-tyrosine kinase inhibitors (EGFR-TKIs) specifically targeting EGFR are deemed as promising probes for the imaging of NSCLC. This study aimed to label icotinib (one kind of EGFR-TKI) with 18F through click reaction to develop a new EGFR-targeting PET probe-18F-icotinib. 18F-icotinib was obtained in 44.81% decay-corrected yield in 100 min synthesis time with 34 GBq/μmol specific activity and>99% radiochemical purity at the end of synthesis. The identity of the product was confirmed by co-injection with 18F-icotinib and 19F-icotinib. The Log P was 1.28 ± 0.04 (n = 6). The tracer displayed excellent stability after incubation for 4 h in vitro. 18F-icotinib showed satisfying binding ability to A549 NSCLC cells, which could be inhibited by icotinib. PET imaging studies demonstrated a specific uptake of the radiotracer (0.90 ± 0.24% ID/g) in A549 tumor-bearing mice, while lower uptake was observed in heart, lung and spleen at 1.5 h post injection. Inmunohistochemical staining confirmed that the A549 tumor was EGFR-positive. Therefore, we considered that 18F-icotinib was a highly promising compound for EGFR-based tumor PET imaging.Graphical abstractGraphical abstract for this article
       
  • Discovery of a new class of valosine containing protein (VCP/P97)
           inhibitors for the treatment of non-small cell lung cancer
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Xueyuan Wang, Enhe Bai, Hui Zhou, Sijia Sha, Hang Miao, Yanru Qin, Zhaogang Liu, Jia Wang, Haoyang Zhang, Meng Lei, Jia Liu, Ou Hai, Yongqiang Zhu Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 μM). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.Graphical abstractGraphical abstract for this article
       
  • Acid-controlled release complexes of podophyllotoxin and etoposide with
           acyclic cucurbit[n]urils for low cytotoxicity
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Fanjie Li, Dan Liu, Xiali Liao, Yulin Zhao, Rongtao Li, Bo Yang The targeted or responsive systems are appealing therapeutic platforms for the development of next-generation precision medications. So, we design and prepare acid-controlled release complexes of podophyllotoxin (POD) and etoposide (VP-16) with pH-labile acyclic cucurbit[n]urils, and their characteristics and inclusion complexation behaviors were investigated via fluorescence spectroscopy, nuclear magnetic resonance and X-ray power diffraction. Cells incubated with complexes have been analyzed by high-content analysis (HCA), and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of POD and VP-16 for clinical application.Graphical abstractHost-1 and drugs combination and in vivo release concept.Graphical abstract for this article
       
  • Magnesium isoglycyrrhizinate suppresses LPS-induced inflammation and
           oxidative stress through inhibiting NF-κB and MAPK pathways in RAW264.7
           cells
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Chunfeng Xie, Xiaoting Li, Jianyun Zhu, Jieshu Wu, Shanshan Geng, Caiyun Zhong Magnesium Isoglycyrrhizinate (MgIG), a novel molecular compound extracted from licorice root, has exhibited greater anti-inflammatory activity and hepatic protection than glycyrrhizin and β-glycyrrhizic acid. In this study, we investigated the anti-inflammatory effect and the potential mechanism of MgIG on Lipopolysaccharide (LPS)-treated RAW264.7 cells. MgIG down-regulated LPS-induced pro-inflammatory mediators and enzymes in LPS-treated RAW264.7 cells, including TNF-α, IL-6, IL-1β, IL-8, NO and iNOS. The generation of reactive oxygen species (ROS) in LPS-treated RAW264.7 cells was also reduced. MgIG attenuated NF-κB translocation by inhibiting IKK phosphorylation and IκB-α degradation. Simultaneously, MgIG also inhibited LPS-induced activation of MAPKs, including p38, JNK and ERK1/2. Taken together, these results suggest that MgIG suppresses inflammation by blocking NF-κB and MAPK signaling pathways, and down-regulates ROS generation and inflammatory mediators.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation and molecular docking of benzimidazole
           grafted benzsulfamide-containing pyrazole ring derivatives as novel
           tubulin polymerization inhibitors
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Yan-Ting Wang, Tian-Qi Shi, Hai-Liang Zhu, Chang-Hong Liu Tubulin-targeting drugs have increasingly become the focus of anticancer drugs research. Twenty-five novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were synthesized and evaluated for bioactivity as potential tubulin polymerization inhibitors. Among them, compound 30 showed the most excellent inhibition against tubulin assembly (IC50 = 1.52 μM) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50 = 0.15, 0.21, 0.33 and 0.17 μM, respectively for A549, Hela, HepG2 and MCF-7). It could also validly induce A549 cell apoptosis, cause cell cycle arrest in G2/M phase and disrupt the cellular microtubule network. These results, along with molecular docking data, provided an important basis for further optimization of compound 30 as a potential anticancer agent.Graphical abstractEffect of compound 30 on cell cycle progression of A549 cells and G2/M-related proteins; 3D diagram of the interaction between compound 30 and the colchicine binding site. A series of novel benzimidazole grafted benzsulfamide-containing pyrazole ring derivatives were designed, synthesized and evaluated for the inhibitory activity against tubulin polymerization and cancer cells. Also the docking simulation of these compounds was conducted.Graphical abstract for this article
       
  • Synthesis and evaluation of Re/99mTc(I) complexes bearing a somatostatin
           receptor-targeting antagonist and labeled via a novel [N,S,O] clickable
           bifunctional chelating agent
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Lauren L. Radford, Dionysia Papagiannopoulou, Fabio Gallazzi, Ashley Berendzen, Lisa Watkinson, Terry Carmack, Michael R. Lewis, Silvia S. Jurisson, Heather M. Hennkens The somatostatin receptor subtype 2 (SSTR2) is often highly expressed on neuroendocrine tumors (NETs), making it a popular in vivo target for diagnostic and therapeutic approaches aimed toward management of NETs. In this work, an antagonist peptide (sst2-ANT) with high affinity for SSTR2 was modified at the N-terminus with a novel [N,S,O] bifunctional chelator (2) designed for tridentate chelation of rhenium(I) and technetium(I) tricarbonyl cores, [Re(CO)3]+ and [99mTc][Tc(CO)3]+. The chelator-peptide conjugation was performed via a Cu(I)-assisted click reaction of the alkyne-bearing chelator (2) with an azide-functionalized sst2-ANT peptide (3), to yield NSO-sst2-ANT (4). Two synthetic methods were used to prepare Re-4 at the macroscopic scale, which differed based on the relative timing of the click conjugation to the [Re(CO)3]+ complexation by 2. The resulting products demonstrated the expected molecular mass and nanomolar in vitro SSTR2 affinity (IC50 values under 30 nM, AR42J cells, [125I]iodo-Tyr11-somatostatin-14 radioligand standard). However, a difference in their HPLC retention times suggested a difference in metal coordination modes, which was attributed to a competing N-triazole donor ligand formed during click conjugation. Surprisingly, the radiotracer scale reaction of [99mTc][Tc(OH2)3(CO)3]+ (99mTc; t½ = 6 h, 141 keV γ) with 4 formed a third product, distinct from the Re analogues, making this one of the unusual cases in which Re and Tc chemistries are not well matched. Nevertheless, the [99mTc]Tc-4 product demonstrated excellent in vitro stability to challenges by cysteine and histidine (≥98% intact through 24 h), along with 75% stability in mouse serum through 4 h. In vivo biodistribution and microSPECT/CT imaging studies performed in AR42J tumor-bearing mice revealed improved clearance of this radiotracer in comparison to a similar [99mTc][Tc(CO)3]-labeled sst2-ANT derivative previously studied. Yet despite having adequate tumor uptake at 1 h (4.9% ID/g), tumor uptake was not blocked by co-administration of a receptor-saturating dose of SS-14. Aimed toward realignment of the Re and Tc product structures, future efforts should include distancing the alkyne group from the intended donor atoms of the chelator, to reduce the coordination options available to the [M(CO)3]+ core (M = Re, 99mTc) by disfavoring involvement of the N-triazole.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of
           4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide
           
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Katsushi Kumata, Akiko Hatori, Tomoteru Yamasaki, Yiding Zhang, Wakana Mori, Masayuki Fujinaga, Lin Xie, Nobuki Nengaki, Ming-Rong Zhang Metabotropic glutamate receptor 2 (mGluR2) has been suggested as a therapeutic target for treating schizophrenia-like symptoms arising from increased glutamate transmission in the human forebrain. However, no reliable positron emission tomography (PET) radiotracer allowing for in vivo visualization of mGluR2 in the human brain is currently available. In this study, we synthesized 4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide ([11C]1) and evaluated its potential as a PET tracer for imaging mGluR2 in the rodent brain. Compound 1, a negative allosteric modulator (NAM) of mGluR2, showed high in vitro binding affinity (IC50: 26 nM) for mGluR2 overexpressed in human cells. [11C]1 was synthesized by O-[11C]methylation of the phenol precursor 2 with [11C]methyl iodide. After the reaction, HPLC purification and formulation, [11C]1 of 7.4 ± 2.8 GBq (n = 8) was obtained from [11C]carbon dioxide of 22.5 ± 4.8 GBq (n = 8) with>99% radiochemical purity and 70 ± 32 GBq/μmol (n = 8) molar activity at the end of synthesis. In vitro autoradiography for rat brains showed that [11C]1 binding was heterogeneously distributed in the cerebral cortex, striatum, hippocampus, and cerebellum. This pattern is consistent with the regional distribution pattern of mGluR2 in the rodent brain. The radioactivity was significantly reduced by self- or MNI-137 (a mGluR2 NAM) blocking. Small-animal PET studies indicated a low in vivo specific binding of [11C]1 in the rat brain. The brain uptake was increased in a P-glycoprotein and breast cancer resistant protein double knockout mouse, when compared to a wild-type mouse. While [11C]1 presented limited potential as an in vivo PET tracer for mGluR2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of anti-CD38 antibody drug conjugate
           based on Daratumumab and maytansinoid
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Xinfu Zhang, Chengxiang Zhang, Xiaomei Yang, Xucheng Hou, Weiyu Zhao, Don Benson, Jianhua Yu, Yizhou Dong Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4, antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s):
       
  • Structure-guided discovery of a novel, potent, and orally bioavailable
           3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): David Sperandio, Vangelis Aktoudianakis, Kerim Babaoglu, Xiaowu Chen, Kristyna Elbel, Gregory Chin, Britton Corkey, Jinfa Du, Bob Jiang, Tetsuya Kobayashi, Richard Mackman, Ruben Martinez, Hai Yang, Jeff Zablocki, Saritha Kusam, Kim Jordan, Heather Webb, Jamie G. Bates, Latesh Lad, Michael Mish The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel acetamide-substituted
           doravirine and its prodrugs as potent HIV-1 NNRTIs
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s): Zhao Wang, Zhao Yu, Dongwei Kang, Jian Zhang, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50 = 59.5 nM) and 8k (EC50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50 = 12.8 μM) and comparable to doravirine (EC50 = 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 February 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 3Author(s):
       
  • Di- and heptavalent nicotinic analogues to interfere with α7
           nicotinic acetylcholine receptors
    • Abstract: Publication date: Available online 17 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yoan Brissonnet, Romulo Araoz, Rui Sousa, Lucie Percevault, Sami Brument, David Deniaud, Denis Servent, Jean-Yves Le Questel, Jacques Lebreton, Sébastien G. Gouin In the field of nicotinic acetylcholine receptors (nAChRs), recognized as important therapeutic targets, much effort has been dedicated to the development of nicotinic analogues to agonize or antagonize distinct homo- and heteropentamers nAChR subtypes, selectively. In this work we developed di- and heptavalent nicotinic derivatives based on ethylene glycol (EG) and cyclodextrin cores, respectively. The compounds showed a concentration dependent inhibition of acetylcholine-induced currents on α7 nAChR expressed by Xenopus oocytes. Interesting features were observed with the divalent nicotinic derivatives, acting as antagonists with varied inhibitory concentrations (IC50) in function of the spacer arm length. The best divalent compounds showed a 16-fold lowered IC50 compared to the monovalent reference (12 vs 195 µM). Docking investigations provide guidelines to rationalize these experimental findings.Graphical abstractGraphical abstract for this article
       
  • Amino acid based prodrugs of a fosmidomycin surrogate as antimalarial and
           antitubercular agents
    • Abstract: Publication date: Available online 17 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Charlotte Courtens, Martijn Risseeuw, Guy Caljon, Louis Maes, Anandi Martin, Serge Van Calenbergh Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential.Graphical abstractGraphical abstract for this article
       
  • Synthesis, Spectroscopic Characterization, Molecular Docking and
           Theoretical Studies (DFT) of
           N-(4-aminophenylsulfonyl)-2-(4-isobutylphenyl) propanamide having
           Potential Enzyme Inhibition Applications
    • Abstract: Publication date: Available online 17 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Amina Asghar, Muhammad Yousuf, Hifsa Mubeen, Rabia Nazir, Kabiru Haruna, Abdulmujeeb T. Onawole, Lubna Rasheed A mutual prodrug (1) of ibuprofen and sulphanilamide has been synthesized with dual activity and improved toxicity profile. The synthesized compound has been characterized by elemental analysis, FT-IR, 1HNMR, 13CNMR and ESI-MS. The molecular geometry of the compound (1) was optimized using density functional theory (DFT/B3LYP) method with the 6-311G(d, p) basis sets in ground state. Geometric parameters (bond lengths, bond angles, torsion angles), vibrational assignments, chemical shifts and thermodynamics of the compound (1) has been calculated theoretically and compared with the experimental data. Comparative AutoDock study of compound (1) with cyclooxygenase enzymes (COX-1 and COX-2) were performed involving docking for possible selectivity of our prodrug within the two Cox enzymes. The highest binding affinities of -8.7 Kcal/mol and -8.1 Kcal/mol has been obtained for COX-1 and COX-2 enzymes respectively. Compound (1) exhibited enhanced anti-inflammatory, anti-ulcer and free radical scavenging activities as compared with the parent drugs. Based on various in vitro and in vivo tests it is suggested that the Compound (1) is more active than the parent drugs. Moreover, LD50 of compound (1) is higher than parent drug i.e. ibuprofen and sulphanilamide suggesting that the synthesized compound is much safer than its parent analogous.Graphical abstractGraphical abstract for this article
       
  • Convenient framework of poly functionalized
           (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides via rearrangements
           as an efficient antibiofilm inhibitors with SAR study
    • Abstract: Publication date: Available online 17 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Perumal Sathiyachandran, Jabastin Jayamanoharan, Vladimir N. Nesterov, Karnam Jayarampillai Rajendra Prasad A simple and one-pot approach for the synthesis of highly functionalized novel (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamide derivatives from different 2-(2',3',4',9'-tetrahydro-carbazol-1'-ylidene)-propanedinitriles and aryl/heteroaryl carbaldehydes via vinylogous aldol reaction. The structures of the molecules were designated by FT-IR, 1H NMR, 13C NMR studies, elemental and X-ray crystallographic analysis. The synthesized pure products have been screened for in vitro antibiofilm inhibitory activity towards antibiotic-resistant pathogenic organisms. All the synthesized compounds showed biofilm inhibition. Promisingly, the moieties 3a, 3d and 3h showed higher antibiofilm activity at biofilm inhibitory concentration (BIC) (200 μg/mL) against bacterial pathogens. Among the three moieties, 3a showed high prospective against E. coli biofilm with minimal and maximal BIC percentage of 32% (10 μg/mL) and 89% (100 μg/mL) and chosen lowest BIC for further evaluation. Also, the 3a generate ROS two fold at 1 h treatment in E. coli biofilm. The 3a exhibited no toxic effect on cell viability upto 75 μg/mL in HEK293 cell lines. The results of the present study reveal that among (E)-2-benzylideno-(Z)-carbazolylideno cyanoacetamides, (E)-2-benzylideno-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-(Z)-α-carbamino-α-cyano-1-ylidene (3a) could be exploited as an excellent antibiofilm agent against carbapenem-resistant E. coli bacteria strains.Graphical abstractGraphical abstract for this article
       
  • Fluorine-18 click radiosynthesis and MicroPET/CT evaluation of a small
           peptide-a potential PET probe for carbonic anhydrase IX
    • Abstract: Publication date: Available online 17 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Lina Jia, Xiao Li, Dengfeng Cheng, Lan Zhang Carbonic anhydrase IX (CA IX) is the first carbonic anhydrase found to be associated with cancer that is over-expressed in a variety of human solid tumors. As a surrogate marker for hypoxia, the expression of CA IX is strongly upregulated in hypoxic tumors by hypoxia and hypoxia-inducible factor 1a (HIF-1a). In our pursuit of a CA IX-specific PET probe, we designed and synthesized a peptide-based CA IX imaging probe by the efficient click reaction of 1,3-dipolar cycloaddition of terminal alkynes and organic azides. The probe 18F-CA IX-P1-4-10 was obtained with a radiochemical yield of 35-45% (n = 5) and radiochemical purity of>99% in 70-80 min (HPLC purification time included). 18F-CAIX-P1-4-10 had good stability in phosphate buffered saline (PBS), but about 51% peptide degradation was detected in new-born calf serum (NBCS) after incubation. Preliminary microPET/CT experiments demonstrated a specific uptake of 18F-CA IX-P1-4-10 in HT29 tumor and the uptake of 18F-CA IX-P1-4-10 was blocked by peptide CA IX-P1-4-10-Yne pretreatment. Immunohistochemical staining and western blotting studies confirmed the HT29 tumor was CA IX-positive which further proved tumor accumulation of 18F-CA IX-P1-4-10 was correlated with CA IX expression. The results suggest that 18F-CA IX-P1-4-10 is a promising PET tracer for the specific imaging of CA IX-expressing tumors at the molecular level.Graphical abstractGraphical abstract for this article
       
  • Synthesis, insecticidal evaluation and mode of action of novel anthranilic
           diamide derivatives containing sulfur moiety as potential ryanodine
           receptor activators
    • Abstract: Publication date: Available online 16 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Feng-Yun Li, Yuan-Hong Wang, Jing-Bo Liu, Yu-Xin Li, Zheng-Ming Li Anthranilic diamide insecticide could control lepidopteran pests by selectively binding and activating insect ryanodine receptors (RyRs), and the unique mode of action is different from other conventional insecticides. In order to discover new anthranilic diamide insecticide as ryanodine receptors activators, a series of 11 novel anthranilic diamides derivatives (Ia-k) were synthesized and confirmed by melting point, 1H NMR, 13C NMR and elemental analyses. The preliminary bioactivity revealed that most title compounds showed moderate to remarkable activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Especially, compounds Ia and If, which exhibited 100% larvicidal activity against oriental armyworm at 1.0 mg L-1, and comparable to that of chlorantraniliprole (100% at 1 mg L-1). If displayed 60% insecticidal activity against diamondback moth at 0.01 mg L-1, better than chlorantraniliprole (45% at 0.01 mg L-1). The preliminary structure activity relationships were discussed. In addition, the calcium imaging experiment indicated that the insect ryanodine receptor is the potential target of If.Graphical abstractGraphical abstract for this article
       
  • Synthesis and Biological Evaluation of Pyrazole Linked
           Benzothiazole-β-Naphthol Derivatives as Topoisomerase I Inhibitors with
           DNA Binding Ability
    • Abstract: Publication date: Available online 16 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Burri Nagaraju, Jeshma Kovvuri, C. Ganesh Kumar, Sunitha Rani Routhu, Md. Adil Shareef, Manasa Kadagathur, Praveen Reddy Adiyala, Sateesh Alavala, Narayana Nagesh, Ahmed Kamal A series of new pyrazole linked benzothiazole-β-naphthol derivatives were designed and synthesized using a simple, efficient and ecofriendly route under catalyst-free conditions in good to excellent yields. These derivatives were evaluated for their cytotoxicity on selected human cancer cell lines. Among those, the derivatives 4j, 4k and 4l exhibited considerable cytotoxicity with IC50 values ranging between 4.63 to 5.54 µM against human cervical cancer cells (HeLa). Structure activity relationship was elucidated by varying different substituents on benzothiazoles and pyrazoles. Further, flow cytometric analysis revealed that these derivatives induced cell cycle arrest in G2/M phase and spectroscopic studies such as UV-visible, fluorescence and circular dichroism studies showed that these derivatives exhibited good DNA binding affinity. Additionally, these derivatives can effectively inhibit the topoisomerase I activity. Viscosity studies and molecular docking studies demonstrated that the derivatives bind with the minor groove of the DNA.Graphical abstractGraphical abstract for this article
       
  • A mitochondria-targeted organic arsenical accelerates mitochondrial
           metabolic disorder and function injury
    • Abstract: Publication date: Available online 16 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Xiao-Yang Fan, Yu-Jiao Liu, Yu-Meng Cai, An-Dong Wang, Yin-Zheng Xia, Yan-Jun Hu, Feng-Lei Jiang, Yi Liu Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug.Graphical abstractGraphical abstract for this article
       
  • Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides
           as novel anti-HCV agents
    • Abstract: Publication date: Available online 16 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shuang Guo, Mingshuo Xu, Qi Guo, Fuqiang Zhu, Xiangrui Jiang, Yuanchao Xie, Jingshan Shen To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a–8c with similar EC50 values (0.20–0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.Graphical abstractGraphical abstract for this article
       
  • Pyrrolomycins as antimicrobial agents. Microwave-assisted organic
           synthesis and insights into their antimicrobial mechanism of action
    • Abstract: Publication date: Available online 16 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Maria Valeria Raimondi, Roberta Listro, Maria Grazia Cusimano, Mery La Franca, Teresa Faddetta, Giuseppe Gallo, Domenico Schillaci, Simona Collina, Ainars Leonchiks, Giampaolo Barone New compounds able to counteract staphylococcal biofilm formation are needed. In this study we investigate the mechanism of action of pyrrolomycins, whose potential as antimicrobial agents has been demonstrated. We performed a new efficient and easy method to use microwave organic synthesis suitable for obtaining pyrrolomycins in good yields and in suitable amount for their in vitro in-depth investigation. We evaluate the inhibitory activity towards Sortase A (SrtA), a transpeptidase responsible for covalent anchoring in Gram-positive peptidoglycan of many surface proteins involved in adhesion and in biofilm formation. All compounds show a good inhibitory activity toward SrtA, having IC50 values ranging from 130 to 300 µM comparable to berberine hydrochloride. Of note compound 1d shows a good affinity in docking experiment to SrtA and exhibits the highest capability to interfere with biofilm formation of S. aureus showing an IC50 of 3.4 nM. This compound is also effective in altering S. aureus murein hydrolase activity that is known to be responsible for degradation, turnover, and maturation of bacterial peptidoglycan and involved in the initial stages of S. aureus biofilm formation.Graphical abstract1d-SrtA ComplexSrtA Docking score: -6.4 kcal/molSrtA FRET IC50: 140 µMBiofilm Inhibition Formation of S.aureus ATCC 25923, IC50: 3.4 nMA three-fold reduced activity of a high-Mw S.aureus murein hydrolaseGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 2Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 2Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 January 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 2Author(s):
       
  • Comprehensive structure-activity-relationship of azaindoles as highly
           potent FLT3 inhibitors
    • Abstract: Publication date: Available online 14 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sebastian H. Grimm, Berend Gagestein, Jordi F. Keijzer, Nora Liu, Ruud H. Wijdeven, Eelke B. Lenselink, Adriaan W. Tuin, Adrianus M.C.H. van den Nieuwendijk, Gerard J.P. van Westen, Constant A.A. van Boeckel, Herman S. Overkleeft, Jacques Neefjes, Mario van der Stelt Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors.Graphical abstractGraphical abstract for this article
       
  • 8-Hydroxy-2-(1H-1,2,3-triazol-1-yl)-1,4-naphtoquinone derivatives
           inhibited P2X7 Receptor-Induced dye uptake into murine Macrophages
    • Abstract: Publication date: Available online 27 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): P.A.F. Pacheco, R.M.S. Galvão, A.F.M. Faria, N.l. Von Ranke, M.S. Rangel, T.M. Ribeiro, M.l. Bello, C.R. Rodrigues, V.F. Ferreira, D.R. da Rocha, R.X. Faria Extracellular adenosine 5′-triphosphate (ATP) triggers the P2X7 receptor (P2X7R) ionic channel to stimulate the release of the interleukin-IL-1β cytokine into macrophages. The current study explored the reaction of six structurally diverse triazole derivatives on P2X7-mediated dye uptake into murine peritoneal macrophages. P2X7R activity determined by ATP-evoked fluorescent dye uptake. Triazole derivatives toxicity measured using dextran rhodamine exclusion based colorimetric assay. A740004 and BBG, both P2X7R antagonist, inhibited ATP-induced dye uptake. In contrast, the derivatives 5a, 5b, 5e, and 5f did not diminish P2X7R activity in concentrations until 100 µM. 5c and 5d analogs caused a potent inhibitory activity on P2X7-induced dye uptake. Dextran Rhodamine exclusion measurements after 24 h of continuous treatment with triazole derivatives indicated a moderated toxicity for all molecules. In conclusion, this study showed that a series of new hybrid 1,2,3-triazolic naphthoquinones reduces P2X7R-induced dye uptake into murine macrophages. In silico analysis indicates a good pharmacokinetic profile and molecular docking results of these analogs indicate the potential to bind into an allosteric site located into the P2X7R pore and juxtaposed with the ATP binding pocket. In this manner, the compounds 5c and 5d may be used as a scaffold for new P2X7R inhibitors with reduced toxicity, and good anti-inflammatory activity.Graphical abstractGraphical abstract for this article
       
  • Glycosyl triazoles as novel insect β-N-acetylhexosaminidase OfHex1
           inhibitors: Design, synthesis, molecular docking and MD simulations
    • Abstract: Publication date: Available online 23 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Lili Dong, Shengqiang Shen, Wei Chen, Huizhe Lu, Dongdong Xu, Shuhui Jin, Qing Yang, Jianjun Zhang The insect enzyme GH20 β-N-acetyl-d-hexosaminidase OfHex1 represents an important chitinolytic enzyme found in the agricultural pest Ostrinia furnacalis (Guenée) and inhibition of this enzyme has been considered a promising strategy for the development of eco-friendly pesticides. In this article, based on the structure of the catalytic domains of OfHex1, a series of novel glycosyl triazoles were designed and synthesized via Cu-catalyzed azide-alkyne [3+2] cycloaddition reaction. To investigate the potency and selectivity of these glycosyl triazoles, the inhibition activities towards OfHex1 and HsHexB (human β-N-acetylhexosaminidase B) were studied. Particularly compound 17c (OfHex1, Ki = 28.68 μM; HsHexB, Ki > 100 μM) exhibited a suitable activity and selectivity against OfHex1. Furthermore, the possible inhibitory mechanisms of 17c with OfHex1 were studied using molecular docking and MD simulations. The structure-activity relationship results as well as the formed binding patterns may provide promising insights into the further development of novel OfHex1 inhibitors.Graphical abstractGraphical abstract for this article
       
  • Clinical aspects of radiolabeled aptamers in diagnostic nuclear medicine:
           A new class of targeted radiopharmaceuticals
    • Abstract: Publication date: Available online 22 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Leila Farzin, Mojtaba Shamsipur, Mohammad Esmaeil Moassesi, Shahab Sheibani Targeted radiopharmaceuticals offer the possibility of improved imaging with reduced side effects. Up to now, a variety of biological receptors such as aptamers have been successfully radiolabeled and applied to diagnostic imaging of cancers. The concept of using radio-labeled aptamers for binding to their targets has stimulated an immense body of research in diagnostic nuclear medicine. These biological recognition elements are single-stranded oligonucleotides that interact with their target molecules with high affinity and specificity in unique three-dimensional structures. Because of their high affinity and specificity, the receptor-binding aptamers labeled with gamma emitters such as 99mTc, 64Cu, 111In, 18F and 67Ga can facilitate the visualization of receptor-expressing tissues noninvasively. Compared to the antibody-based radiopharmaceuticals, the radiolabeled aptamers provide a number of advantages for clinical diagnostics including high stability, low cost, and ease of production and modification, low immunogenicity and, especially, superior tissue penetration because of their smaller size. In this review, we present recent progresses and challenges in aptamer-based diagnostic radiopharmaceuticals and highlight some representative applications of aptamers in nuclear medicine.Graphical abstractGraphical abstract for this article
       
  • Structural and computational basis for potent inhibition of glutamate
           carboxypeptidase II by carbamate-based inhibitors
    • Abstract: Publication date: Available online 14 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Cyril Barinka, Zora Novakova, Niyada Hin, Daniel Bím, Dana V. Ferraris, Bridget Duvall, Gabriel Kabarriti, Reiji Tsukamoto, Milos Budesinsky, Lucia Motlova, Camilo Rojas, Barbara S. Slusher, Tibor András Rokob, Lubomír Rulíšek, Takashi Tsukamoto A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-l-glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII’s preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt a nearly identical binding mode while (R,S)-carbamate analog 8 containing a d-leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of
           5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as
           potent β2-adrenoceptor agonists
    • Abstract: Publication date: Available online 1 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Gang Xing, Li Pan, Ce Yi, Xiaoran Li, Xinyue Ge, Ying Zhao, Yichuang Liu, Jinyan Li, Anthony Woo, Bin Lin, Yuyang Zhang, Maosheng Cheng A series of novel β2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β2-adrenoceptor agonistic effects and high β2/β1-selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.Graphical abstractGraphical abstract for this article
       
  • Synthesis and anti-HCV activity of β-D-2'-deoxy-2'-α-chloro-2'-β-fluoro
           and β-D-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides and their
           phosphoramidate prodrugs
    • Abstract: Publication date: Available online 9 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Reuben Ovadia, Ahmed Khalil, Hao Li, Coralie De Schutter, Seema Mengshetti, Shaoman Zhou, Leda Bassit, Steven J. Coats, Franck Amblard, Raymond F. Schinazi We report herein the synthesis and evaluation of a series of β-D-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-D-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides along with their corresponding phosphoramidate prodrugs. Key intermediates, lactols 11 and 12, were obtained by a diastereoselective fluorination of protected 2-deoxy-2-chloro/bromo-ribonolactones 7 and 8. All synthesized nucleosides and prodrugs were evaluated with a hepatitis C virus (HCV) subgenomic replicon system.Graphical abstractGraphical abstract for this article
       
  • Discovery of highly potent V600E-B-RAF kinase inhibitors: Molecular
           Modeling Study
    • Abstract: Publication date: Available online 7 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hamadeh Tarazi, Mohammed I. El-Gamal, Chang-Hyun Oh A series of 20 triarylpyrazole derivatives containing amide or urea linker have been synthesized. Their in vitro antiproliferative activity against NCI-60 cancer cell lines panel has been reported. Upon investigating the mechanism of action at molecular level, compound 1e showed selectivity and potency against V600E-B-RAF (IC50 = 390 nM). Herein, we decided to investigate the potency of the other nineteen target compounds against V600E-B-RAF. This led to discovery of several more potent compounds against that kinase. The IC50 values of compounds 1g-i and 2f-i were within the range of 7∼47 nM. Among them, the diarylurea compound 1i was the most potent (IC50 = 7 nM). Results of docking and molecular dynamic analysis suggested the presence of consistent binding mode among our compound series with type-IIA class of inhibition pattern. Subsequently, the contribution of structural features to bioactivity were explored by means of QSAR analysis, where such effort led to the development of predictive QSAR model with significant statistical parameters (R2 = 0.912, F = 38.64, Q2LOO = 0.834, Q2LMO = 0.816, s = 0.334). Furthermore, pharmacophoric features existed among our compound series were investigated employing molecular interaction field (MIF) analysis, which led to the development of partial least squares model consisted of four latent variables (4LV-PLS) with statistical parameters of (R2acc. = 0.98, Q2acc. = 0.81).Graphical abstractGraphical abstract for this article
       
  • Identification of novel uracil derivatives incorporating benzoic acid
           moieties as highly potent Dipeptidyl Peptidase-IV inhibitors
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Junli Huang, Xiaoyan Deng, Siru Zhou, Na Wang, Yujun Qin, Liuwei Meng, Guobao Li, Yuhua Xiong, Yating Fan, Ling Guo, Danni Lan, Junhao Xing, Weizhe Jiang, Qing Li Dipeptidyl peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S2’ site, a series of novel uracil derivatives1a-l and 2a-i incorporating benzoic acid moieties at the N3 position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC50 = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antimicrobial activities of N6-hydroxyagelasine analogs and
           revision of the structure of ageloximes
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Britt Paulsen, Kim Alex Fredriksen, Dirk Petersen, Louis Maes, An Matheeussen, Ali-Oddin Naemi, Anne Aamdal Scheie, Roger Simm, Rui Ma, Baojie Wan, Scott Franzblau, Lise-Lotte Gundersen (+)-N6-Hydroxyagelasine D, the enantiomer of the proposed structure of (–)-ageloxime D, as well as N6-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N6-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N6-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5). The spectral data of N6-hydroxyagelasine D did not match those reported for ageloxime D before. Hence, a revised structure of ageloxime D was proposed. Basic hydrolysis of agelasine D gave (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, a compound with spectral data in full agreement with those reported for (–)-ageloxime D.Graphical abstractGraphical abstract for this article
       
  • Discovery of two novel branched peptidomimetics containing endomorphin-2
           and RF9 pharmacophores: Synthesis and neuropharmacological evaluation
    • Abstract: Publication date: Available online 4 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ting Zhang, Zhenglan Han, Xuerui Shi, Weidong Zhao, Zilong Wang, Run Zhang, Biao Xu, Mengna Zhang, Qinqin Zhang, Jian Xiao, Hanwen Zhu, Ting Zheng, Quan Fang It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Identification of Novel Coumaperine Derivatives for
           Inhibition of Human 5-LOX: Antioxidant, Pseudoperoxidase and Docking
           Studies
    • Abstract: Publication date: Available online 3 January 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Subramani Muthuraman, Shweta Sinha, C.S. Vasavi, Kamran Manzoor Waidha, Biswarup Basu, Punnagai Munussami, M.M. Balamurali, Mukesh Doble, Rajendran Saravana Kumar 5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC50 values are 2.1 ± 0.2 µM and 2.3 ± 0.2 µM respectively, and are comparable to zileuton, IC50 = 1.4 ± 0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.Graphical abstractPepper based compounds developed as potent 5-LOX inhibitors. Coumaperine derivatives substituted with multiple methoxy and hydroxyl groups exhibited high 5-LOX inhibition with good drug likeliness and reduced toxicity. Antioxidant, pseudoperoxidase and molecular docking studies were conducted to understand the mode of inhibition.Graphical abstract for this article
       
  • Caged-xanthone from Cratoxylum formosum ssp. pruniflorum inhibits
           malignant cancer phenotypes in multidrug-resistant human A549 lung cancer
           cells through down-regulation of NF-κB
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Chutima Kaewpiboon, Nawong Boonnak, Natpaphan Yawut, Sirichat Kaowinn, Young-Hwa Chung Our recent study reported that multidrug-resistant (MDR) human A549 lung cancer cells (A549RT-eto) with the elevated expression of NF-κB showed epithelial–mesenchymal transition (EMT), increasing spheroid formation and elevating the expression levels of stemness-related factors, including Oct4, Nanog, Sox2, Bmi1, and Klf4. Therefore, when new therapeutic agents targeting these malignant cancer cells were explored, we found that caged-xanthone (CX) isolated from the roots of Cratoxylum formosum ssp. pruniflorum diminished the expression of NF-κB, P-glycoprotein (P-gp) protein levels, cell migration and invasion, and sphere-forming ability of A549RT-eto cells. To address the role of NF-κB in these malignant cancer features, we treated A549RT-eto cells with NF-κB siRNAs in the present work. We found that the knockdown of NF-κB inhibited EMT and sphere formation. Furthermore, co-treatment with CX and NF-κB siRNA accelerated the death of apoptotic cells through the decrease of P-gp protein levels. These results suggest that NF-κB was involved in malignant cancer phenotypes and MDR in A549RT-eto cells. Taken together, our findings suggest that CX can be a potential therapeutic agent for the treatment of malignant tumor cells.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis, Insecticidal Activity and Molecular Docking of
           Doramectin Derivatives
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Qi Zhang, Ping Bai, Cheng Zheng, Yao Cheng, Tao Wang, Xiaoxia Lu A series of new doramectin derivatives containing carbamate, ester and sulfonate were synthesized, and their structures were characterized by 1H and 13C nuclear magnetic resonance (NMR) and high-resolution mass spectrum (HRMS). Their insecticidal activities against oriental armyworm, diamondback moth, and corn borer were evaluated and compared with the parent doramectin and commercial avermectins, metolcarb, fenpropathrin. Among all compounds, three compounds (3a, 3g and 3h) showed excellent insecticidal effect. In particular, compound 3g containing cyclopropyl carbamate against oriental armyworm, diamondback moth, and corn borer, exhibited the most promising insecticidal activity with the final mortality rate of 66.67%, 36.67%, 40.00% at the concentration of 12.5 mg/L, respectively. The LC50 values of 3g were 5.8859, 22.3214, and 22.0205 mg/L, showing 6.74, 2.23, 2.21-fold higher potency than parent doramectin (LC50 values of 39.6907, 49.7736, and 48.6129 mg/L) and 6.83, 1.93, 3.36-fold higher potency than commercial avermectins (LC50 values of 40.2489, 42.9922, and 73.9508 mg/L). Additionally, molecular docking simulations revealed that 3g displayed stronger hydrogen-bonding action in binding with the GABA receptor than parent doramectin, which were crucial for keeping high insecticidal activity. The present work demonstrated that these compounds containing alkyl carbamate group could be considered as potential candidates for the development of novel pesticides in the future.Graphical abstractGraphical abstract for this article
       
  • Synthesis of new α-aminophosphonates: evaluation as anti-inflammatory
           agents and QSAR studies
    • Abstract: Publication date: Available online 31 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ivan Romero-Estudillo, José Luis Viveros-Ceballos, Obed Cazares-Carreño, Angelina González-Morales, Berenice Flores de Jesús, Misael López-Castillo, Rodrigo Said Razo-Hernández, Gabriela Castañeda-Corral, Mario Ordóñez In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95 %), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9-34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as
           potent mutant isocitrate dehydrogenase-1 inhibitors
    • Abstract: Publication date: Available online 23 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Xiaoqi Liu, Yuanyuan Hu, Anhui Gao, Meng Xu, Lixin Gao, Lei Xu, Yubo Zhou, Jianrong Gao, Qing Ye, Jia Li A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.Graphical abstractGraphical abstract for this article
       
  • Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine
           inhibitors toward butyrylcholinesterase in alzheimer's disease
    • Abstract: Publication date: Available online 23 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Peterson de Andrade, Susimaire P. Mantoani, Paulo Sérgio Gonçalves Nunes, Carlos Roca Magadán, Concepción Pérez, Danilo Jordão Xavier, Elza Tiemi Sakamoto Hojo, Nuria E. Campillo, Ana Martínez, Ivone Carvalho Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.Graphical abstractGraphical abstract for this article
       
  • Discovery of a crystalline sulforaphane analog with good solid-state
           stability and engagement of the Nrf2 pathway in vitro and in vivo
    • Abstract: Publication date: Available online 21 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Jeffrey Boehm, Roderick Davis, Claudia E. Murar, Tindy Li, Brent McCleland, Shuping Dong, Hongxing Yan, Jeffrey Kerns, Christopher J. Moody, Anthony J. Wilson, Alan P. Graves, Mary Mentzer, Hongwei Qi, John Yonchuk, Jen-Pyng Kou, Joseph Foley, Yolanda Sanchez, Patricia L. Podolin, Brian Bolognese, Catherine Booth-Genthe The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.Graphical abstractGraphical abstract for this article
       
  • Synthesis of 5a,5a’-dicarba-D-glucobioses from conformationally
           restricted carbaglucosyl triflates using SN2-type inversion with
           carbaglucosyl nucleophiles
    • Abstract: Publication date: Available online 19 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Naoya Tateda, Katsumi Ajisaka, Masaji Ishiguro, Tatsuo Miyazaki Novel carbohydrate mimics were designed which contain two 5a-carba-D-glucose residues, one each at reducing and nonreducing end, and thus these mimics are 5a,5a’-dicarba-D-glucobioses. Dicarbadisaccharides have attractive features such as stability against endogenous degradative enzymes and being resistant to glycation reactions such as the Maillard reaction. For the synthesis of dicarba-β-D-isomaltose derivatives, the carbaglucosyl triflate locked in 4C1 conformation was synthesized by protecting with butane-2,3-diacetal group or benzylidene group. Then, 5a,5a’-dicarba-β-D-maltose and 5a,5a’-dicarba-α,β-D-trehalose were synthesized by the SN2-type inversion reaction using 4,6-O-benzylidene carbaglucosyl triflate with 4-OH and 1-OH carba-β-D-glucose derivatives, respectively, and similarly 5a,5a’-dicarba-α-D-isomaltose with 6-OH carba-α-D-glucose derivative.Graphical abstractGraphical abstract for this article
       
  • Leucoflavonine, a new bioactive racemic flavoalkaloid from the leaves of
           Leucosceptrum canum
    • Abstract: Publication date: Available online 16 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ling Feng, Yu Zhang, Yan-Chun Liu, Yan Liu, Shi-Hong Luo, Chun-Shuai Huang, Sheng-Hong Li A new flavoalkaloid racemate, leucoflavonine (1), together with its flavonoid precursor pectolinarigenin (2), was isolated from leaves of Leucosceptrum canum collected from Tibet. Its structure was established by comprehensive spectroscopic analysis. Chrial separation of the enantiomers of 1 was achieved, and their absolute configurations were determined as S-(+)- and R-(−)-leucoflavonines ((+)-1a and (−)-1b) by comparison of their computational and experimental optical rotations. Biological assays indicated that both (+)-1a and (−)-1b exhibited inhibitory activity against acetylchlorinesterase (AChE) in vitro (IC50 = 68.0 ± 8.6 and 18.3 ± 1.8 μM, respectively). Moreover, (−)-1b displayed cytotoxicity against human hepatoma cells HepG2 (IC50 = 52.9 ± 3.6 μM), and inhibited the production of interleukelin-2 (IL-2) in Jurkat cells (IC50 = 16.5 ± 0.9 μM), while (+)-1a showed no obvious activity in these assays.Graphical abstractGraphical abstract for this article
       
  • Tripeptide analogues of MG132 as protease inhibitors
    • Abstract: Publication date: Available online 14 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ashok D. Pehere, Steven Nguyen, Sarah K. Garlick, Danny W. Wilson, Irene Hudson, Matthew J. Sykes, James D. Morton, Andrew D. Abell The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1–3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.Graphical abstractGraphical abstract for this article
       
  • α-Glucosidase inhibition activity and in silico study of
           2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one, a synthetic derivative of
           flavone
    • Abstract: Publication date: Available online 13 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Surya N. Meena, Ujjwal kumar, Mayuri M. Naik, Sanjeev S. Ghadi, Santosh G. Tilve A synthetic flavone derivative 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one (BDC) was synthesized by the one pot reaction method and assessed for α-glucosidase inhibitory activity. The BDC demonstrated dose dependent inhibition of α-glucosidase activity. A maximum inhibition (99.3±0.26 %) of α-glucosidase was observed at 27.6 µM. The maximum α-glucosidase inhibitory activity depicted by BDC 27.6 µM concentration was 22.4 fold over the maximum inhibition observed with acarbose (97.72±0.59 % at 669.57 µM), a standard commercial anti-diabetic drug. In contrast to acarbose that depicted competitive type inhibition, kinetic studies of α-glucosidase inhibition by BDC demonstrated non-competitive inhibition with Km of 0.71 mM-1 and a Vmax of 0.028 mmol/min. In silico studies suggest allosteric interaction of BDC with α-glucosidase at a minimum binding energy (ΔG) of -8.64 kcal/mol and Ki of 465.3 nM, whereas, acarbose interacted at the active site of α-glucosidase with ΔG of -9.23 kcal/mol and Ki of 172 nM. Thus BDC significantly inhibited α-glucosidase in comparison to acarbose. Moreover, BDC has been endorsed for drug likeness by evaluating it as per Lipinski rule of five. Thus, BDC can be a lead compound for the management of type-2 diabetes mellitus.Graphical abstractGraphical abstract for this article
       
  • Evaluation of a non-prime site substituent and warheads combined with a
           decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor
    • Abstract: Publication date: Available online 12 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Kouji Ohnishi, Yasunao Hattori, Kazuya Kobayashi, Kenichi Akaji A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CLpro, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CLpro when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CLpro but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.Graphical abstractGraphical abstract for this article
       
  • 4-Aryl-5-carbamoyl-3-isoxazolols as competitive antagonists of insect GABA
           receptors: synthesis, biological activity, and molecular docking studies
    • Abstract: Publication date: Available online 12 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Genyan Liu, Huaguang Li, Jiaying Shi, Wenjie Wang, Kenjiro Furuta, Di Liu, Chunqing Zhao, Fumiyo Ozoe, Xiulian Ju, Yoshihisa Ozoe Competitive antagonists (CAs) of ionotropic GABA receptors (GABARs) reportedly exhibit insecticidal activity and have potential for development as novel insecticides for overcoming emerging resistance to traditional GABAR-targeting insecticides. Our previous studies demonstrated that 4,5-disubstituted 3-isoxazolols or 3-isothiazolols are an important class of insect GABAR CAs. In the present study, we synthesized a series of 4-aryl-5-carbamoyl-3-isoxazolols and examined their antagonism of insect GABARs expressed in Xenopus oocytes. Several of these 3-isoxazolols exhibited potent antagonistic activities against housefly and common cutworm GABARs, with IC50 values in the low-micromolar range in both receptors. 4-(3-Amino-4-methylphenyl)-5-carbamoyl- 3-isoxazolol (3u) displayed the highest antagonism, with IC50 values of 2.0 and 0.9 μM in housefly and common cutworm GABARs, respectively. Most of the synthesized 3-isoxazolols showed moderate larvicidal activities against common cutworms, with more than 50% mortality at 100 μg/g. These results indicate that 4-monocyclic aryl-5-carbamoyl-3-isoxazolol is a promising scaffold for insect GABAR CA discovery and provide important information for the design and development of GABAR-targeting insecticides with a novel mode of action.Graphical abstractGraphical abstract for this article
       
  • Synthesis, Antioxidant Activity and Cytotoxicity of
           N-Functionalized Organotellurides
    • Abstract: Publication date: Available online 11 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Pamela T. Bandeira, Mara C. Dalmolin, Mariana M. de Oliveira, Karine C. Nunes, Francielle P. Garcia, Celso V. Nakamura, Alfredo R.M. de Oliveira, Leandro Piovan The use of antioxidants is the most effective means to protect the organism against cellular damage caused by oxidative stress. In this context, organotellurides have been described as promising antioxidant agents for decades. Herein, a series of N-functionalized organotellurium compounds has been tested as antioxidant and presented remarkable activities by three different in vitro chemical assays. They were able to reduce DPPH radical with IC50 values ranging from 5.08 to 19.20 µg mL−1, and some of them also reduced ABTS+ radical and TPTZ-Fe3+ complex in ABTS+ and FRAP assays, respectively. Initial structure-activity relationship discloses that the nature of N-substituent strongly influenced both activity and cytotoxicity of the studied compounds. Furthermore, radical scavenging activities of N-functionalized organotellurides have been compared with those of their selenilated congeners, demonstrating that the presence of tellurium atom has an essential role in antioxidant activity.Graphical abstractGraphical abstract for this article
       
  • Discovery of Potent, Low-absorbable Sodium-Dependent Glucose Cotransporter
           1 (SGLT1) Inhibitor SGL5213 for Type 2 Diabetes Treatment
    • Abstract: Publication date: Available online 11 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Shoichi Kuroda, Yohei Kobashi, Takahiro Oi, Kenichi Kawabe, Fumiyasu Shiozawa, Lisa Okumura-Kitajima, Mami Sugisaki-Kitano, Fusayo Io, Koji Yamamto, Hiroyuki Kakinuma A new series of C-phenyl D-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges. Compounds 34d and 34j were poorly absorbed, but the absorbed compounds were mainly excreted in bile. Thus, smaller amounts of persistent residue in the kidneys were observed. Since 34d exerted a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in SD rats, this compound (SGL5213) could be a clinical candidate for the treatment of type 2 diabetes.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of radioiodinated
           benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor
           receptor β (PDGFRβ) imaging
    • Abstract: Publication date: Available online 11 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Nurmaya Effendi, Kenji Mishiro, Takeshi Takarada, Daisuke Yamada, Ryuichi Nishii, Kazuhiro Shiba, Seigo Kinuya, Akira Odani, Kazuma Ogawa Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-{piperazin-1-yl}quinoline (5a) and 4-{2-[5-(2-Methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-{piperazin-1-yl}quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1 h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.Graphical abstractGraphical abstract for this article
       
  • In Silico, NMR and Pharmacological Evaluation of an Hydroxyoxindole
           Cholinesterase Inhibitor
    • Abstract: Publication date: Available online 10 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Patrícia Bacalhau, Luís Fernandes, M. Rosário Martins, Fátima Candeias, Elisabete P. Carreiro, Óscar López, A. Teresa Caldeira, Jane Totobenazara, Rita C. Guedes, Anthony J. Burke From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 μM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)- 1 to determine its potential for use as an alternative ChE inhibitor for the treatment of AD. The strategy adopted included in vivo and ex vivo studies with mouse models, molecular modelling and Saturation Transfer Difference (STD) NMR studies.Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min-1.mg-1) than donepezil (0.112 µmol.min-1. mg-1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min-1.mg-1).Graphical abstractGraphical abstract for this article
       
  • Antiviral activities of Janus-type nucleosides and their related
           oxime-intermediates
    • Abstract: Publication date: Available online 8 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Jiang Liu, Hang Zhao, Xinglong Zhou, Yang He, Qianming Chen Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for patients with compromised immunity. When combined with the emergence of resistance due to the long-term use of classical antiviral agents, these threats make novel therapeutics for HSV a clinically necessity. We therefore designed and synthesized a series of Janus-type nucleosides by combining the natural genetic alphabets into a singular nucleoside structural unit. We also synthesized a series of new compounds and systematically evaluated their antiviral activity and structure-antiviral activity relationship. The results indicated that both nucleosides and their related intermediates exhibited high anti-HSV-1 activity. Compounds HY17 and HY19, in particular, possessed excellent anti-HSV-1 activity with IC50 values of 0.05 and 0.04 µg/mL, respectively. They also showed broad-spectrum antiviral activity against a multitude of diverse viruses, such as HSV-2, influenza virus A (H3N2), CVB3, HBV, HCV, and HPV. These results suggest that once their mechanisms are fully elucidated, these compounds will prove to be promising candidates as antiviral agents.Graphical abstractGraphical abstract for this article
       
  • Flavone-based natural product agents as new lysine-specific demethylase 1
           inhibitors exhibiting cytotoxicity against breast cancer cells in vitro
    • Abstract: Publication date: Available online 7 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Xiao Xu, Wenhui Peng, Cuiyun Liu, Sixuan Li, Jiali Lei, Zhen Wang, Lingyi Kong, Chao Han Lysine-specific demethylase 1 (LSD1) has recently emerged as a therapeutic target for cancer. However, almost all LSD1 inhibitors developed to date are chemo-synthesised molecules. In this study, the LSD1 inhibitory activity of 12 natural flavones, including four aglycones and their corresponding monoglycosides and diglucosides, was evaluated. Based on the structure–activity relationships, LSD1 inhibition activity was greater for flavonoid monoglycosides than their aglycones lacking the sugar moiety. The effects of isoquercitrin, which exhibited optimal LSD1 inhibitory activity, on cancer cell properties were evaluated. Isoquercitrin induced the expression of key proteins in the mitochondrial-mediated apoptosis pathway and caused apoptosis in LSD1-overexpressing MDA-MB-231 cells via the inhibition of LSD1. These findings suggest that natural LSD1 inhibitors, and particularly isoquercitrin, are promising for cancer treatment.Graphical abstractGraphical abstract for this article
       
  • Synthesis of novel pyrazoline derivatives and the evaluation of death
           mechanisms involved in their antileukemic activity
    • Abstract: Publication date: Available online 7 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Natália Marceli Stefanes, Jéssica Toigo, Mariana Franzoni Maioral, Amanda Virtuoso Jacques, Louise Domeneghini Chiaradia-Delatorre, Daiane Mari Perondi, Amanda Abdalla Biasi Ribeiro, Álisson Bigolin, Iris Mattos Santos Pirath, Bruna Ficher Duarte, Ricardo José Nunes, Maria Cláudia Santos-Silva Malignant neoplasms are one of the leading causes of death worldwide and hematologic malignancies, including acute leukemia (AL) is one of the most relevant cancer types. Current available chemotherapeutics are associated with high morbidity and mortality rates, therefore, the search for new molecules with antitumor activity, specific and selective for neoplastic cells, became a great challenge for researchers in the oncology field. As pyrazolines stand out in the literature for their great variety of biological activities, the aim of this study was to synthesize and evaluate the antileukemic activity of five new pyrazoline derivatives. All pyrazolines showed adequate physicochemical properties for a good oral bioavailability. The two unpublished and most effective pyrazoline derivatives have been selected for further experiments. These compounds are highly selective for leukemic cells when compared to non-neoplastic cells and did not cause lysis on human red blood cells. Additionally, selected pyrazolines induced cell cycle arrest at G0/G1 phase and decreased cell proliferation marker KI67. Apoptotic cell death induced by selected pyrazolines was confirmed by morphological analysis, assessment of phosphatidylserine residue exposure and DNA fragmentation. Several factors indicate that both intrinsic and extrinsic apoptosis occurred. These were: increased FasR expression; the predominance of Bax in relation to Bcl-2; the loss of mitochondrial membrane potential; AIF release; decreased expression of survivin (an antiapoptotic protein); and the activation of caspase-3. The selected pyrazolines were also found to be cytotoxic against neoplastic cells collected from the peripheral blood and bone marrow of patients with different subtypes of acute leukemia.Graphical abstractGraphical abstract for this article
       
  • Pyrrolidinone-bearing methylated and halogenated benzenesulfonamides as
           inhibitors of carbonic anhydrases
    • Abstract: Publication date: Available online 6 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Irena Vaškevičienė, Vaida Paketurytė, Nikita Pajanok, Šarūnas Žukauskas, Birutė Sapijanskaitė, Kristina Kantminienė, Vytautas Mickevičius, Asta Zubrienė, Daumantas Matulis Two series of benzenesulfonamides bearing methyl groups at ortho/ortho or meta/ortho positions and a pyrrolidinone moiety at para position were synthesized and tested as inhibitors of the twelve catalytically active human carbonic anhydrase (CA) isoforms. Observed binding affinities were determined by fluorescent thermal shift assay and intrinsic binding affinities representing the binding of benzenesulfonamide anion to the Zn(II)-bound water form of CA were calculated. Introduction of dimethyl groups into benzenesulfonamide ring decreased the binding affinity to almost all CA isoforms, but gained in selectivity towards one CA isoform. A chloro group at the meta position of 2,6-dimethylbenzensulfonamide derivatives did not influence the binding to CA I, but it increased the affinity to all other CAs, especially, CA VII and CA XIII (up to 500 fold). The compounds may be used for further development of CA inhibitors with higher selectivity to particular CA isoforms.Graphical abstractGraphical abstract for this article
       
  • Elucidating the mode of action for thiophene-based organic D-π-A
           sensitizers for use in photodynamic therapy
    • Abstract: Publication date: Available online 6 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Shinichiro Fuse, Miori Takizawa, Shinichi Sato, Shigetoshi Okazaki, Hiroyuki Nakamura Photodynamic therapy (PDT) is a non-invasive, selective, and cost-effective cancer therapy. The development of readily accessible templates that allow rapid structural modification for further improvement of PDT remains important. We previously reported thiophene-based organic D-π-A sensitizers consisted of an electron-donating (D) moiety, a π -conjugated bridge (π) moiety, and an electron-accepting (A) moiety as valuable templates for a photosensitizer that can be used in PDT. Our preliminary structure-activity relationship study revealed that the structure of the A moiety significantly influences its phototoxicity. In this study, we evaluated the photoabsorptive, cellular uptake, and photo-oxidizing abilities of D-π -A sensitizers that contained different A moieties. The level of phototoxicity of the D-π -A sensitizers was rationalized by considering those three abilities. In addition, we observed the ability of amphiphilic sensitizers containing either a carboxylic acid or an amide in an A moiety to form aggregates that penetrate cells mainly via endocytosis.Graphical abstractGraphical abstract for this article
       
  • Synthetic Approaches to Isocarbacyclin and Analogues as Potential
           Neuroprotective Agents Against Ischemic Stroke
    • Abstract: Publication date: Available online 6 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ghina'a I. Abu Deiab, Mitchell P. Croatt Isocarbacyclin is a valuable synthetic analogue of prostacyclin with potential neuroprotective effects for the treatment of ischemic stroke. Herein, we describe the synthesis of isocarbacyclin and bicyclic analogues in only 7 to 10 steps, with the ω-side chain diversified at a late stage. A combination of new reaction design, function-oriented synthesis, and late-stage diversification led to a series of compounds that were tested for their neuroprotective activities. Efforts toward the synthesis of tricyclic analogues of isocarbacyclin, using the same combination of metal-catalyzed reactions, is also described.Graphical abstractGraphical abstract for this article
       
  • Stability and properties of Z-DNA containing artificial nucleobase
           2’-O-methyl-8-methyl guanosine
    • Abstract: Publication date: Available online 6 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Thananjeyan Balasubramaniyam, Takumi Ishizuka, Yan Xu We synthesized several DNA oligonucleotides containing one or several 2’-O-methyl-8-methyl guanosine (m8Gm) and demonstrated that these oligonucleotides not only stabilize the Z-DNA with a wide range of sequences under low salt conditions but also possess high thermal stability. Using artificial nucleobase-containing oligonucleotides, we studied the interaction of the Zα domain with Z-DNA. Furthermore, we showed that the m8Gm-contained oligonucleotides allow to study the photochemical reaction of Z-DNA.Graphical abstractGraphical abstract for this article
       
  • Synthesis of amides from
           (E)-3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid and substituted
           
    • Abstract: Publication date: Available online 6 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Santosh K. Rath, Samsher Singh, Sunil Kumar, Naiem A. Wani, Rajkishor Rai, Surrinder Koul, Inshad A. Khan, Payare L. Sangwan Inhibitors for NorA efflux pump of Staphylococcus aureus have attracted the attention of many researchers towards the discovery and development of novel efflux pump inhibitors (EPIs). In an attempt to find specific potent inhibitors of NorA efflux pump of S. aureus, a total of 15 amino acid conjugates of 3-(1-chloro-3,4-dihydronaphthalen-2-yl)acrylic acid (4-18) were synthesized using a simple convenient synthetic approach and bioevaluated against NorA efflux pump. Two compounds 7 and 8 (each having MEC of 1.56 µg/mL) were found to restore the activity of ciprofloxacin through reduction of the MIC elucidated by comparing the ethidium bromide efflux in dose dependent manner in addition to ethidium bromide efflux inhibition and accumulation study using NorA overexpressing strain SA-1199B. Most potent compounds among these were able to restore the antibacterial activity of ciprofloxacin completely against SA-1199B. Structure activity relationship (SAR) studies and docking study of potent compounds 7 and 8 could elucidate the structural requirements necessary for interaction with the NorA efflux pumps. On the whole, compounds 7 and 8 have ability to reverse the NorA efflux mediated resistance and could be further optimized for development of potent efflux pump inhibitors.Graphical abstractGraphical abstract for this article
       
  • Metronidazole Aryloxy, Carboxy and Azole Derivatives: Synthesis,
           Anti-tumor Activity, QSAR, Molecular Docking and Dynamics Studies
    • Abstract: Publication date: Available online 4 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Ehsan Faghih-Mirzaei, Salehe Sabouri, Leila Zeidabadinejad, Salman AbdolahRamazani, Mehdi Abaszadeh, Arash Khodadadi, Mohadeseh Shamsadinipour, Mandana Jafari, Somayeh Pirhadi A series of novel metronidazole aryloxy, carboxy and azole derivatives has been synthesized and their cytotoxic activities on three cancer cell lines were evaluated by MTT assay. Compounds 4m, 4l and 4d showed most potent cytotoxic activity (IC50s < 100µg/mL). Apoptosis was also detected for these compounds by flow cytometry. Docking studies were performed in order to propose the probable target protein. In the next step, molecular dynamics simulation was carried out on the proposed target protein, focal adhesion kinase (FAK, PDB code: 2ETM), bound to compound 4m. As, 4m showed a potent cytotoxic activity and an acceptable apoptotic effect, it can be a potential anticancer candidate that may work through inhibition of FAK.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of selective CYP1B1 inhibitor via dearomatization of
           α-naphthoflavone
    • Abstract: Publication date: Available online 3 December 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Makoto Kubo, Keiko Yamamoto, Toshimasa Itoh Selective cytochrome P450 (CYP) 1B1 inhibition has potential as an anticancer strategy that is unrepresented in the current clinical arena. For development of a selective inhibitor, we focused on the complexity caused by sp3-hybridized carbons and synthesized a series of benzo[h]chromone derivatives linked to a non-aromatic B-ring using α-naphthoflavone (ANF) as the lead compound. Ring structure comparison suggested compound 37 as a suitable cyclohexyl-core with improved solubility. Structural evolution of 37 produced the azide-containing cis-49a, which had good properties in three important respects: (1) selectivity for CYP1B1 over CYP1A1 and CYP1A2 (120-times and 150-times, respectively), (2) greater inhibitory potency of more than 2 times that of ANF, and (3) improved solubility. The corresponding aromatic B-ring compound 59a showed low selectivity and poor solubility. To elucidate the binding mode, we performed X-ray crystal structure analysis, which revealed the interaction mode and explained the subtype selectivity of cis-49a.Graphical abstractGraphical abstract for this article
       
  • Anti-biofilm and anti-adherence properties of novel cyclic dipeptides
           against oral pathogens
    • Abstract: Publication date: Available online 29 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Gaëlle Simon, Christopher Bérubé, Normand Voyer, Daniel Grenier Microorganisms embedded in a biofilm are significantly more resistant to antimicrobial agents and the defences of the human immune system, than their planktonic counterpart. Consequently, compounds that can inhibit biofilm formation are of great interest for novel therapeutics. In this study, a screening approach was used to identify novel cyclic dipeptides that have anti-biofilm activity against oral pathogens. Five new active compounds were identified that prevent biofilm formation by the cariogenic bacterium Streptococcus mutans and the pathogenic fungus Candida albicans. These compounds also inhibit the adherence of microorganisms to a hydroxylapatite surface. Further investigations were conducted on these compounds to establish the structure-activity relationship, and it was deduced that the common cleft pattern is required for these molecules to act effectively against biofilms. To our knowledge, this is the first report of the anti-biofilm and anti-adherence properties of synthetic cyclic dipeptides.Graphical abstractGraphical abstract for this article
       
  • Electron injection from mitochondrial transcription factor A to DNA
           associated with thymine dimer photo repair
    • Abstract: Publication date: Available online 29 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Fumitaka Hashiya, Shinji Ito, Hiroshi Sugiyama Electron transfer through π-stacked arrays of double-stranded DNA contributes to the redox chemistry of bases, including guanine oxidation and thymine–thymine dimer repair by photolyase. 5-Bromouracil is an attractive photoreactive thymine analogue that can be used to investigate electron transfer in DNA, and is a useful probe for protein–DNA interaction analysis. In the present study using BrU we found that UV irradiation facilitated electron injection from mitochondrial transcription factor A into DNA. We also observed that this electron injection could lead to repair of a thymine–thymine dimer.Graphical abstractGraphical abstract for this article
       
  • Lamellarin-inspired potent topoisomerase I inhibitors with the
           unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold
    • Abstract: Publication date: Available online 28 November 2018Source: Bioorganic & Medicinal ChemistryAuthor(s): Tsutomu Fukuda, Yusuke Nanjo, Masahiro Fujimoto, Kenyu Yoshida, Yuko Natsui, Fumito Ishibashi, Fumiyasu Okazaki, Hideto To, Masatomo Iwao A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.Graphical abstractGraphical abstract for this article
       
 
 
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