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  Subjects -> CHEMISTRY (Total: 886 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (619 journals)
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CHEMISTRY (619 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 27)
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African Journal of Bacteriology Research     Open Access  
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African Journal of Pure and Applied Chemistry     Open Access   (Followers: 8)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
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American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 21)
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American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 39)
Angewandte Chemie     Hybrid Journal   (Followers: 170)
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Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
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Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 87)
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C - Journal of Carbon Research     Open Access   (Followers: 3)
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Chemistry Letters     Full-text available via subscription   (Followers: 44)
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Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
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ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
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Cogent Chemistry     Open Access   (Followers: 2)
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Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
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        1 2 3 4 | Last

Journal Cover
Bioorganic & Medicinal Chemistry Letters
Journal Prestige (SJR): 0.81
Citation Impact (citeScore): 3
Number of Followers: 87  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3162 journals]
  • Graphical abstract TOC
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s):
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s):
       
  • A Copper10-Paclitaxel crystal; a medicinally active drug
           delivery platform
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Thomas Manning, Christopher Slaton, Nia Myers, Pavan D. Patel, Domonique Arrington, Zalak Patel, Dennis Phillips, Greg Wylie, Russell Goddard Paclitaxel is a well-known cancer drug that functions as a mitotic inhibitor. This work focuses on a copper based crystal that encapsulates the pharmaceutical agent and serves as a drug delivery agent. A Copper10-Pacitaxil1 chloride (CU10PAC1) complex is synthesized and tested against the National Cancer Institute’s sixty cell line panel. The 10:1 ratio results in a crystal that was examined by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spec (MALDI-TOF-MS), Scanning Electron Microscopy (SEM) and Proton (1H) and Carbon (13C) Nuclear Magnetic Resonance (NMR). The potential attributes of a copper based crystal as an in vivo drug carrier for Paclitaxel are discussed.Graphical abstractPaclitaxel is a well-known cancer drug that functions as a mitotic inhibitor. This work focuses on a copper based crystal that encapsulates the pharmaceutical agent and serves as a drug delivery agent. A Copper10-Pacitaxil1 chloride (CU10PAC1) complex is synthesized and tested against the National Cancer Institute’s sixty cell line panel. The 10:1 ratio results in a crystal that was examined by Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS), Scanning Electron Microscopy (SEM) and Proton (1H) and Carbon (13C) Nuclear Magnetic Resonance (NMR). The potential attributes of a copper based crystal as an in vivo drug carrier for Paclitaxel are discussed.Graphical abstract for this article
       
  • In vitro and in vivo characterization of a novel, highly
           potent p53-MDM2 inhibitor
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Andrea Vaupel, Philipp Holzer, Stephane Ferretti, Vito Guagnano, Joerg Kallen, Robert Mah, Keiichi Masuya, Stephan Ruetz, Caroline Rynn, Achim Schlapbach, Thérèse Stachyra, Stefan Stutz, Milen Todorov, Sébastien Jeay, Pascal Furet Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.Graphical abstractGraphical abstract for this article
       
  • Quantitative structure–activity relationship analysis using deep
           learning based on a novel molecular image input technique
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Yoshihiro Uesawa Quantitative structure–activity relationship (QSAR) analysis uses structural, quantum chemical, and physicochemical features calculated from molecular geometry as explanatory variables predicting physiological activity. Recently, deep learning based on advanced artificial neural networks has demonstrated excellent performance in the discipline of QSAR research. While it has properties of feature representation learning that directly calculate feature values from molecular structure, the use of this potential function is limited in QSAR modeling. The present study applied this function of feature representation learning to QSAR analysis by incorporating 360° images of molecular conformations into deep learning. Accordingly, I successfully constructed a highly versatile identification model for chemical compounds that induce mitochondrial membrane potential disruption with the external validation area under the receiver operating characteristic curve of ≥0.9.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of cyclopropane-based conformationally restricted
           GABA analogues as selective inhibitors for betaine/GABA transporter 1
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Akihiro Suemasa, Mizuki Watanabe, Takaaki Kobayashi, Hiroe Suzuki, Hayato Fukuda, Masabumi Minami, Satoshi Shuto We previously designed and synthesized a series of cyclopropane-based conformationally restricted analogues of γ-aminobutyric acid (GABA). The study demonstrated that the critical conformation of the analogues that selectively active to betaine/GABA transporter 1 (BGT1) subtype is the trans-syn-form, in which the amino and carboxyl groups are in trans-configuration and the cyclopropane ring and the carboxyl group are in syn-arrangement. In this study, we designed and synthesized cyclopropane-based GABA analogues, which were conformationally restricted in the trans-syn-form by cyclopropylic strain based on the stereochemistry of the carbon adjacent to cyclopropane. Their conformation was confirmed as the syn-form by calculations and NMR studies, and their pharmacological evaluation clarified that compounds 11a and 11d had the BGT1 selectivity, although their inhibitory effects were insufficient.Graphical abstractGraphical abstract for this article
       
  • Hybrids of arenobufagin and benzoisoselenazol reducing the cardiotoxicity
           of arenobufagin
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Wen Hou, Zhi-Xing Huang, Hong-Gui Xu, Jing Lin, Dong-Mei Zhang, Qun-Long Peng, Hui Lin, Yi-Qun Chang, Long-Hai Wang, Zhe Yao, Ping-Hua Sun, Wei-Min Chen Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.Graphical abstractA series of novel benzoisoselenazol-containing arenobufagin hybrids were designed, synthesized and their in vitro cytotoxicity for cancer cell lines and AC16 cell line, as well as their ROS scavenge activities were evaluated. Among them, 6d and 6f exhibited ROS scavenge activities and less cardiotoxcity.Graphical abstract for this article
       
  • Synthesis and biological evaluation of novel
           5,6-dihydropyrimido[4,5-f]quinazoline derivatives as potent CDK2
           inhibitors
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Xiaoxia Hu, Hui Zhao, Youzhi Wang, Zhan Liu, Bainian Feng, Chunlei Tang As serine/threonine kinase, the cyclin dependent kinase 2 (CDK2) is a promising target for various diseases such as cerebral hypoxia, cancer, and neurodegenerative diseases. Here we reported the structure-based synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as CDK2 inhibitors, which exhibited potent CDK2 inhibitory activities, as well as anticancer activities in low concentration against two human cancer cell lines (MCF-7 and HCT116). In particular, compounds 11a and 11f (IC50 values of 0.11 and 0.09 μM for CDK2, respectively) have demonstrated significantly inhibitory potency against CDK2 and have showed great inhibitory activities against MCF-7 and HCT116 cell lines.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of isoxazolyl-sulfonamides: A
           non-cytotoxic scaffold active against Trypanosoma cruzi, Leishmania
           amazonensis and Herpes Simplex Virus
    • Abstract: Publication date: 1 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 20Author(s): Rafael da Rosa, Lara Almida Zimmermann, Milene Höehr de Moraes, Naira Fernanda Zanchett Schneider, Alice Duarte Schappo, Claudia Maria de Oliveira Simões, Mario Steindel, Eloir Paulo Schenkel, Lílian Sibelle Campos Bernardes In this study we report the synthesis, characterization, biological evaluation, and druglikeness assessment of a series of 20 novel isoxazolyl-sulfonamides, obtained by a four-step synthetic route. The compounds had their activity against Trypanosoma cruzi, Leishmania amazonensis, Herpes Simplex Virus type 1 and cytotoxicity evaluated in phenotypic assays. All compounds have drug-like properties, showed low cytotoxicity and were promising regarding all other biological activities reported herein, especially the inhibitory activity against T. cruzi. The compounds 8 and 16 showed significant potency and selectivity against T. cruzi (GI50 = 14.3 µM, SI > 34.8 and GI50 = 11.6 µM, SI = 29.1, respectively). These values, close to the values of the reference drug benznidazole (GI50 = 10.2 µM), suggest that compounds 8 and 16 represent promising candidates for further pre-clinical development targeting Chagas disease.Graphical abstractGraphical abstract for this article
       
  • Synthesis of novel benzbromarone derivatives designed to avoid metabolic
           activation
    • Abstract: Publication date: Available online 15 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tomoyuki Ohe, Ryutaro Umezawa, Yumina Kitagawara, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Akiko Abe, Shuichi Sekine, Kousei Ito, Kentaro Okunushi, Hanae Morio, Tomomi Furihata, Naohiko Anzai, Tadahiko Mashino We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.Graphical abstractGraphical abstract for this article
       
  • Structure-guided design and synthesis of isoflavone analogs of GW4064 with
           potent lipid accumulation inhibitory activities
    • Abstract: Publication date: Available online 15 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Rongmao Qiu, Guoshun Luo, Xuerong Cai, Linyi Liu, Mingqi Chen, Deying Chen, Qidong You, Hua Xiang Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.Graphical abstractGraphical abstract for this article
       
  • An investigation on 4-thiazolidinone derivatives as dual inhibitors of
           aldose reductase and protein tyrosine phosphatase 1B, in the search for
           potential agents for the treatment of type 2 diabetes mellitus and its
           complications
    • Abstract: Publication date: Available online 15 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Rosanna Maccari, Antonella Del Corso, Paolo Paoli, Ilenia Adornato, Giulia Lori, Francesco Balestri, Mario Cappiello, Alexandra Naß, Gerhard Wolber, Rosaria Ottanà Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1–17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.Graphical abstractGraphical abstract for this article
       
  • Synthesis of enamino-2-oxindoles via conjugate addition between α-azido
           ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis
           inducing studies
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Niggula Praveen Kumar, Yogesh Vanjari, Sowjanya Thatikonda, Venkatesh Pooladanda, Pankaj Sharma, Balasubramanian Sridhar, Chandraiah Godugu, Ahmed Kamal, Nagula Shankaraiah A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screened for their in vitro cytotoxic potential on selected human cancer cell lines such as colon, lung, breast, and cervical cancer cells. Among them, representative compounds 3a, 3h, 3k, 3p, 3w and 3x showed notable cytotoxicity profile with IC50 values ranging from 1.40 ± 0.10 to 28.7 ± 0.36 µM. Compound 3k displayed most potent cytotoxicity against lung cancer (NCI-H460) cells with an IC50 value of 1.40 ± 0.10 µM. 3k also arrested the G2/M phase of the cell cycle and induced distinctive apoptotic features on lung cancer cells. The apoptosis induction is supported by various cellular assays such as AO/EB, DAPI, and DCFDA staining studies including clonogenic assay. Extent of apoptosis was also analyzed by Annexin binding and JC-1 staining. Moreover, this method is amenable for the generation of a library of new class of stable bioactive enamino-2-oxindoles.Graphical abstractGraphical abstract for this article
       
  • Hemin-incorporated nanoflowers as enzyme mimics for colorimetric detection
           of foodborne pathogenic bacteria
    • Abstract: Publication date: Available online 10 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kui-Yu Wang, Sheng-Jun Bu, Chuan-Jing Ju, Chang-Tian Li, Zhong-Yi Li, Ye Han, Cheng-You Ma, Cheng-Yu Wang, Zhuo Hao, Wen-Sen Liu, Jia-Yu Wan Rapid, sensitive and point-of-care detection of foodborne pathogenic bacteria is essential for food safety. In this study, we found that hemin-concanavalin A hybrid nanoflowers (HCH nanoflowers), as solid mimic peroxidase, could catalyze oxidation of 2,2’-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) in the presence of H2O2 to a green-colored product. HCH nanoflowers, integrating the essential functions of both biological recognition and signal amplification, meet the requirements of signal labels for colorimetric immunoassay of bacteria. In view of the excellent peroxidase mimetic catalytic activity of HCH nanoflowers, a colorimetric biosensing platform was newly constructed and applied for sensitive detection of foodborne Escherichia coli O157:H7 (E.coli O157:H7). The corresponding detection limits was as low as 4.1 CFU/mL with wide linear ranges (101−106 CFU/mL).Graphical abstractGraphical abstract for this article
       
  • Discovery and structure-activity-relationship study of novel imidazole
           cyclopropyl amine analogues for mutant isocitric dehydrogenase 1 (IDH1)
           inhibitors
    • Abstract: Publication date: Available online 4 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Qiangang Zheng, Ziqi Chen, Huixin Wan, Shuai Tang, Yan Ye, Yuan Xu, Lei Jiang, Jian Ding, MeiyuGeng, Min Huang, Ying Huang The discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of 4-chloro-2H-thiochromenes
           featuring nitrogen-containing side chains as potent antifungal agents
    • Abstract: Publication date: Available online 19 June 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Dan-Jiao Wang, Zhuang Hou, Hang Xu, Ran An, Xin Su, Chun Guo A series of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains were designed, synthesized and tested in vitro for their antifungal activities. The results of preliminary antifungal tests showed that most target compounds exhibited good inhibitory activities against Candida albicans, Cryptococcus neoformans, Candida tropicalis. Notably, compounds 10e and 10y showed most potent activity in vitro against a variety of fungal pathogens with low MICs. Meanwhile, low cytotoxicity on mammalian cells has been observed for compounds 10e and 10y in the tested concentrations by the MTT assay. Therefore, the 4-chloro-2H-thiochromenes with nitrogen-containing groups provide new lead structures in the search for novel antifungal agents.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of an 18F-labeled boramino acid analog of
           aminosuberic acid for PET imaging of the antiporter system xC −
    • Abstract: Publication date: Available online 8 June 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Milena Čolović, Etienne Rousseau, Zhengxing Zhang, Joseph Lau, Chengcheng Zhang, Hsiou-Ting Kuo, Hua Yang, Paul Schaffer, François Bénard, Kuo-Shyan Lin In this study, we synthesized 18F-ASu-BF3, a close boramino acid analog of 5-[18F]fluoro-aminosuberic acid (18F-ASu), via 18F-19F isotope exchange reaction and evaluated its potential for imaging with positron emission tomography (PET). 18F-ASu-BF3 was stable in mouse plasma and taken up into PC3 prostate cancer cells via the system xC− amino acid transporter. The continuous use of isoflurane for anesthesia during dynamic imaging acquisition slowed down the excretion of 18F-ASu-BF3 and enabled visualization of PC3 tumor xenografts in mice. In contrast, no tumor visualization was observed from static images of 18F-BF3-ASu due to its rapid renal excretion mediated in part by the organic anion transporter. Our data indicate that the pharmacokinetics of amino acids could be altered after being converted into their boramino acid analogs. Therefore, care should be taken when using the boramino acid strategy to design and prepare 18F-labeled tracers for imaging amino acid transporters/receptors with PET.Graphical abstractGraphical abstract for this article
       
  • Semisynthesis of ent-norstrobane diterpenoids as potential
           inhibitor for factor Xa
    • Abstract: Publication date: Available online 17 May 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jianbin Wang, He Ma, Hongzheng Fu A semisynthesis of two ent-strobane diterpenoids strobols C (7) and D (14) was accomplished via a Wagnar-Meerwein rearrangement. Compounds 7, 14, and the intermediate products were evaluated for their inhibition on factor Xa (FXa). Among all the compounds screened for FXa inhibitory activity, three compounds 6, 7, and 9 showed significant inhibitory activities with IC50 values of 1067 ± 164, 81 ± 11, 1023 ± 89 nM, respectively. The inhibitory activity on FXa described in this study highlight the importance of structural modification based on natural products in the development of FXa inhibitors.Graphical abstractGraphical abstract for this article
       
  • Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for
           cancer therapy
    • Abstract: Publication date: Available online 3 May 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Zhong-Chang Wang, Fa-Qian Shen, Meng-Ru Yang, Ling-Xia You, Li-Zhi Chen, Hai-Liang Zhu, Ya-Dong Lu, Fan-Lei Kong, Ming-Hua Wang MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1–E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC50 = 2.80 μM for MMP-2 and IC50 = 5.6 μM for MMP-8), compared to the positive drug CMT-1 (IC50 = 1.29 μM). Compounds (E1–E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1–E18 may provide a research basis for the development of new agents against cancer.Graphical abstractInteractions between compound E16 and MMP-2 in a three dimentional stereogram.Graphical abstract for this article
       
  • Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of
           sitagliptin derivatives as new multifunctional antidiabetic agents
    • Abstract: Publication date: Available online 15 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yundong Xie, Lihua Shao, Qiutang Wang, Yue Bai, Zizhang Chen, Na Li, Yanhong Xu, Yiping Li, Guangde Yang, Xiaoli Bian Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP- IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC50 value of 0.060 μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.Graphical abstractGraphical abstract for this article
       
  • Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors
           for cancer therapy
    • Abstract: Publication date: Available online 15 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sandeep Rana, Yogesh A. Sonawane, Margaret A. Taylor, Smitha Kizhake, Muhammad Zahid, Amarnath Natarajan We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution in the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.Graphical abstractGraphical abstract for this article
       
  • Synthesis, in vitro and in vivo evaluation of 2-aryl-4H-chromene and
           
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Alexander A. Spasov, Denis A. Babkov, Dmitry V. Osipov, Vladlen G. Klochkov, Diana R. Prilepskaya, Maxim R. Demidov, Vitaly A. Osyanin, Yuri N. Klimochkin Herein we report a study of novel arylchromene derivatives as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties. Novel inhibitors were identified via simple stepwise in silico screening, efficient synthesis, and biological evaluation. It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically. A lead compound identified through screening inhibits yeast α-glucosidase with IC50 of 62.26 µM and prevents postprandial hyperglycemia in rats at 2.2 mg/kg dose.Graphical abstractGraphical abstract for this article
       
  • Discovery and optimization of a novel series of pyrazolyltetrahydropyran
           N-type calcium channel (Cav 2.2) blockers for the treatment of pain
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mark J. Wall, Nalin L. Subasinghe, Michael P. Winters, Mary Lou Lubin, Michael F.A. Finley, Ning Qin, Michael R. Brandt, Michael P. Neeper, Craig R. Schneider, Raymond W. Colburn, Christopher M. Flores, Zhihua Sui A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.Graphical abstractGraphical abstract for this article
       
  • Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2)
           inhibitors possessing a key intramolecular hydrogen bond — Part 2
    • Abstract: Publication date: Available online 12 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Daniel G.M. Shore, Zachary K. Sweeney, Alan Beresford, Bryan K. Chan, Huifen Chen, Jason Drummond, Andrew Gill, Tracy Kleinheinz, Xingrong Liu, Andrew D. Medhurst, Edward G. McIver, John G. Moffat, Haitao Zhu, Anthony A. Estrada The discovery of disease-modifying therapies for Parkinson’s Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.Graphical abstractGraphical abstract for this article
       
  • Synthesis, modification, and cytotoxic evaluation of 2,3-secotriterpenic
           β-ketoesters
    • Abstract: Publication date: Available online 11 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Daria V. Eroshenko, Gulnaz F. Krainova, Anastasia V. Konysheva, Maksim V. Dmitriev, Victoria V. Grishko A set of β-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid β-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC50 3.07–3.61 µM) against the HCT 116, MS, RD TE32 cancer cells. The studies of the cytotoxic mechanism enabled elucidating the fact that treatment of the HCT 116 cells with compound 4 for 18 h leads to induction of apoptosis in a dose-dependent manner. This observation was confirmed by registration of chromatin condensation, by the fluorescence increased during Annexin V-FITC staining, and by appearance of a sub-G0 peak in the cell cycle analysis with DAPI. Compound 4 also inhibited migration of cancer cells in the wound healing assay.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of novel hybrids between
           4-anilinoquinazolines and substituted triazoles as potent cytotoxic agents
           
    • Abstract: Publication date: Available online 11 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Giang Le Nhat Thuy, Thuy Van Dinh, Hai Pham-The, Hung Nguyen Quang, Nga Nguyen Thi, Tuyet Anh Dang Thi, Phuong Hoang Thi, Tu Anh Le Thi, Ha Thanh Nguyen, Phuong Nguyen Thanh, Trung Le Duc, Tuyen Van Nguyen In this research several series of novel dioxygenated ring fused 4-anilinoquinazolines (10a-d) and 4-anilinoquinazoline-substituted triazole hybrid compounds (11-14) have been designed and synthesized. Their biological significance was highlighted by evaluating in vitro for anticancer activities, wherein several compounds displayed excellent activity specifically against three human cancer cell lines (KB, epidermoid carcinoma; HepG2, hepatoma carcinoma; SK-Lu-1, non-small lung cancer). Especially, compound 13a exhibited up to 100-fold higher cytotoxicity in comparison with erlotinib. Docking the most cytotoxic compounds (11d, 13a, 13b, and 14c) into the ATP binding site of different EGFR tyrosine kinase domains was perfomed to predict the analogous binding mode of these compounds to the EGFR targets.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of novel
           aminopyrimidinylisoindolines as AXL kinase inhibitors
    • Abstract: Publication date: Available online 11 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Min Jung Choi, Eun Joo Roh, Wooyoung Hur, So Ha Lee, Taebo Sim, Chang-Hyun Oh, Sun-Hwa Lee, Jong Seung Kim, Kyung Ho Yoo A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC50 values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC50 = < 0.00050 μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC50 = < 0.00050, 0.025, and 0.050 μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI50 = 0.10 μM) related to acute myeloid leukemia (AML).Graphical abstractSix compounds showed potent inhibitory activities against AXL kinaseMost compounds showed good antiproliferative activities against HeLa cell line1u exhibited extremely excellent efficacy (IC50 = < 0.00050 μM) against AXL kinase1u showed the best combination of enzyme inhibitory and antiproliferative activitiesGraphical abstract for this article
       
  • Integrating thin film microfluidics in developing a concise synthesis of
           DGJNAc: A potent inhibitor of α-N-acetylgalctosaminidases
    • Abstract: Publication date: Available online 11 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Siobhán S. Wills, Colin L. Raston, Keith A. Stubbs A simple synthesis, which utilizes a thin film microfluidic reactor for a problematic step, of a potent inhibitor of α-N-acetylhexosaminidases, DGJNAc, has been developed.Graphical abstractGraphical abstract for this article
       
  • Discovery of
           5-(2-Chloro-4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-tetrazole as
           potent and orally efficacious S-Nitrosoglutathione reductase (GSNOR)
           inhibitors for the potential treatment of COPD
    • Abstract: Publication date: Available online 10 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nagarajan Muthukaman, Sanjay Deshmukh, Shital Tondlekar, Macchindra Tambe, Dnyandeo Pisal, Neelam Sarode, Siddharth Mhatre, Samitabh Chakraborti, Daisy Shah, Vikram M. Bhosale, Abhay Kulkarni, Mahamad Yunnus A. Mahat, Satyawan B. Jadhav, Girish S. Gudi, Neelima Khairatkar-Joshi, Laxmikant A. Gharat Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure–activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: < 15 nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.Graphical abstractGraphical abstract for this article
       
  • Evaluation of the Effect of 2’-O-Methyl, Fluoro Hexitol, Bicyclo and
           Morpholino Nucleic Acid Modifications on Potency of GalNAc Conjugated
           Antisense Oligonucleotides in Mice
    • Abstract: Publication date: Available online 10 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Thazha P. Prakash, Jinghua Yu, Garth A. Kinberger, Audrey Low, Michaela Jackson, Frank Rigo, Eric E. Swayze, Punit P. Seth The potency of antisense oligonucleotide (ASO) drugs has significantly improved in the clinic after exploiting asialoglycoprotein receptor (ASGR) mediated delivery to hepatocytes. To further this technology, we evaluated the structure-activity relationships of oligonucleotide chemistry on in vivo potency of GalNAc-conjugated Gapmer ASOs. GalNAc conjugation improved potency of ASOs containing 2’-O-methyl (2’-O-Me), 3’-fluoro hexitol nucleic acid (FHNA), locked nucleic acid (LNA), and constrained ethyl bicyclo nucleic acid (cEt BNA) 10-20-fold compared to unconjugated ASOs. We further demonstrate that GalNAc conjugation improves activity of 2’-O-(2-methoxyethyl) (2’-O-MOE) and Morpholino ASOs designed to correct splicing of survival motor neuron (SMN2) pre-mRNA in liver after subcutaneous administration. GalNAc modification thus represents a viable strategy for enhancing potency of ASO with diverse nucleic acid modifications and mechanisms of action for targets expressed in hepatocytes.Graphical abstractGraphical abstract for this article
       
  • Monodisperse oligoethylene glycols modified Propofol prodrugs
    • Abstract: Publication date: Available online 10 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tao Deng, Xianglan Mao, Yu Li, Shaowei Bo, Zhigang Yang, Zhong-Xing Jiang The low water solubility of Propofol resulted in complicated formulation and adverse effects during its clinical application. To improve its water solubility and maintain its anesthetic effects, Propofol prodrugs with monodisperse oligoethylene glycols as solubility enhancer were designed and synthesized. Monodisperse oligoethylene glycols enable the concise manipulation of water solubility, biocompatibility and anesthetic effects. Through the physicochemical and biological assay, a few water soluble prodrugs of Propofol were identified as promising anesthetic to overcome the drawbacks associated with Propofol.Graphical abstractMonodisperse oligoethylene glycol was employed to concisely manipulate the water solubility and anesthetic effects of Propofol, an anesthetics with poor solubility and side effects.Graphical abstract for this article
       
  • Sentulic acid isolated from Sandoricum koetjape Merr attenuates
           lipopolysaccharide and interferon gamma co-stimulated nitric oxide
           production in murine macrophage RAW264 cells
    • Abstract: Publication date: Available online 9 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tomohiro Itoh, Kousuke Katsurayama, Mai Efdi, Masayuki Ninomiya, Mamoru Koketsu A seco-triterpenoid, sentulic acid (SA) isolated from Sandoricum koetjape Merr attenuated nitric oxide (NO) production following co-stimulation with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in RAW264.7 macrophage cells. The mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IFNγ, interleukin (IL)-6, and IL-12 in LPS/IFNγ co-stimulated RAW264.7 cells also decreased upon SA treatment. To determine the molecular mechanisms underlying the inhibitory effect of SA on LPS/IFNγ-induced NO production in RAW264.7 cells, we further analyzed Toll-like receptor (TLR) signaling by western blotting. The expression of TLR4 and IFN signaling molecules in cells treated with SA was significantly suppressed compared to that in cells not treated with SA. Additionally, SA inhibited the binding of LPS to the TLR4 receptor in RAW264.7 cells stimulated with Alexa Fluor 488-conjugated LPS. These results demonstrate that SA attenuates NO production after LPS/IFNγ co-stimulation in RAW264.7 cells by inhibiting the binding of LPS to TLR4. Our findings suggest that SA is beneficial for the treatment of inflammatory diseases.Graphical abstractA seco-triterpenoid, sentulic acid isolated from Sandoricum koetjape Merr attenuated lipopolysaccharidesand interferon-gamma co-stimulated nitric oxide production in RAW264.7 macrophage cells through the inhibiting of LPS binding to Toll-like receptor 4.Graphical abstract for this article
       
  • Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors
           bearing pyrimidine and N-substituted aromatic piperazine
    • Abstract: Publication date: Available online 9 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): KaiJun Jin, YaLi Sang, Erik De Clercq, Christophe Pannecouque, Ge Meng A novel series of substituted piperazine-1-yl-pyrimidine derivatives were designed and synthesized as a new type of HIV-1 non-nucleoside inhibitors. Various N-substituted aromatic groups were incorporated into the piperazine ring through a simple and practical route to investigate the biological activity of these target compounds against wild-type and resistant strains of HIV-1. All of the target compounds were also evaluated as HIV-1 reverse transcriptase inhibitors in MT-4 cell cultures. The biological results showed that six of these compounds displayed inhibitory activities against the wild-type strain, among of which 7q and 7t were found to be the two most active analogues possessing EC50 values of 31.50 μM and 3.36 μM, respectively. Molecular modeling studies of 7q provide valuable information for developing new anti-HIV-1 inhibitors.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 21Author(s):
       
  • Discovery and lead identification of quinazoline-based BRD4 inhibitors
    • Abstract: Publication date: 15 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 21Author(s): Shyh-Ming Yang, Daniel J. Urban, Makoto Yoshioka, Jeffrey W. Strovel, Steven Fletcher, Amy Q. Wang, Xin Xu, Pranav Shah, Xin Hu, Matthew D. Hall, Ajit Jadhav, David J. Maloney A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 15 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 21Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 November 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 21Author(s):
       
  • Novel Tacrine–pyridinium Hybrid Reactivators of
           Organophosphorus-inhibited Acetylcholinesterase: Synthesis, Molecular
           Docking, and In Vitro Reactivation Study
    • Abstract: Publication date: Available online 4 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jinwoo Kim, Yashwardhan R. Malpani, Jooyun Lee, Jin Soo Shin, Soo Bong Han, Young-Sik Jung First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine–pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2–C7) were prepared (Scheme 1, 5a–f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1 μM concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1 μM concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (n=2–5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1 μM concentrations. Molecular modeling carried out using Maestro v10.2 predicted that the binding mode of 5c has the optimal distance (5.02 Å) and orientation for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited AChE.Graphical abstractGraphical abstract for this article
       
  • Design of novel lipidated peptidomimetic conjugates for targeting EGFR
           heterodimerization in HER2 + cancer
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Himgauri Naik, Ted Gauthier, Sitanshu Singh, Seetharama Jois The human epidermal growth factor receptor (EGFR) family is known to be involved in cell signaling pathways. The extracellular domain of EGFR consists of four domains, of which domain II and domain IV are known to be involved in the dimerization process. Overexpression of these receptors is known to play a significant role in heterodimerization of these receptors leading to the development of cancer. We have designed peptidomimetic molecules to inhibit the EGFR heterodimerization interaction that have shown antiproliferative activity and specificity for HER2-positive cancer cell lines. Among these, a peptidomimetic, compound 5, exhibited antiproliferative activity at low nanomolar concentrations in HER2-overexpressing cancer cell lines. To improve the stability of this peptidomimetic, we have designed and synthesized a novel conjugate of peptidomimetic compound 5 with a lipid, stearic acid. The antiproliferative activity of this conjugate was evaluated in HER2-positive cancer cell lines. Results suggested that the conjugate exhibited selective antiproliferative activity in HER2-overexpressing breast and lung cancer cell lines and was able to block HER2:HER3 heterodimerization. Also, the conjugate showed improved stability with a half-life of 5 h in human serum compared to the half-life of 2 h for parent compound 5. The binding affinity of the conjugate to HER2 protein was evaluated by SPR analysis, and the mode of binding of the lipid conjugate to domain IV of HER2 protein was demonstrated by docking analysis. Thus, this novel lipid conjugate can be used to target HER2-overexpressing cancers.Graphical abstractGraphical abstract for this article
       
  • b-Annulated 1,4-dihydropyridines as Notch inhibitors
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jorge E. Gómez-Galeno, Cecilia Hurtado, Jiongjia Cheng, Ceren Yardimci, Mark Mercola, John R. Cashman The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50 ≈ 2.5 μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50 = 0.36 μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50 = 0.13 μM, or about 20-fold the potency of 1.Graphical abstractGraphical abstract for this article
       
  • Discovery of selective urokinase plasminogen activator (uPA) inhibitors as
           a potential treatment for multiple sclerosis
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Imadul Islam, Shendong Yuan, Christopher W. West, Marc Adler, Ulrich Bothe, Judi Bryant, Zheng Chang, Kieu Chu, Kumar Emayan, Giovanna Gualtieri, Elena Ho, David Light, Cornell Mallari, John Morser, Gary Phillips, Caralee Schaefer, Drew Sukovich, Marc Whitlow, Deborah Chen, Brad O. Buckman We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.Graphical abstractGraphical abstract for this article
       
  • Antiplasmodial flavanones and a stilbene from Carpha glomerata
    • Abstract: Publication date: Available online 4 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Namki Cho, Ana Lisa Valenciano, Yongle Du, Jason Clement, Maria B. Cassera, Michael Goetz, David G.I. Kingston Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC50 values of 5.2 ± 0.6, 3.4 ± 0.4, and 6.7 ± 0.8 µM against the drug-resistant Dd2 strain of Plasmodium falciparum. In addition the prenylated stilbene 5 also showed good activity, with IC50 5.8 ± 0.7 µM.Graphical abstractGraphical abstract for this article
       
  • Iodine-mediated oxidative cyclization for one pot synthesis of new
           8-hydroxyquinaldine derivatives containing a N-phenylpyrazole moiety as
           pesticidal agents
    • Abstract: Publication date: Available online 1 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ting Xu, Xiaoguang Wang, Qian Zhang, Jiangping Fan, Liu Liu, Mingzhu Liu, Haojie Zhang, Jing Li, Yong Guo In continuation of our research aimed at discovery and development of new pesticidal agents, a series of new 8-hydroxyquinaldine derivatives containing a N–phenylpyrazole moiety were prepared and their structures were characterized by 1H NMR, IR, ESI-MS and mp. Meanwhile, an efficient way of using iodine-mediated oxidative cyclization for one pot synthesis of these 8-hydroxyquinaldine derivatives containing a N–phenylpyrazole moiety was developed. The bioassay showed that compounds 8g and 9f exhibited potent pesticidal activities against both Mythimna separata Walker and Plutella xylostella Linnaeus. The structure–activity relationships were also discussed.Graphical abstractGraphical abstract for this article
       
  • Improved Potency and Reduced Toxicity of the Antifungal Peptoid AEC5
           Through Submonomer Modification
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Madyson P. Middleton, Scott A. Armstrong, Kevin L. Bicker As proteolytically stable peptidomimetics, peptoids could serve as antifungal agents to supplement a therapeutic field wrought with toxicity issues. We report the improvement of an antifungal peptoid, AEC5, through an iterative structure-activity relationship study. A sarcosine scan was used to first identify the most pharmacophorically important peptoid building blocks of AEC5, followed by sequential optimization of each building block. The optimized antifungal peptoid from this study, β-5, has improved potency towards Cryptococcus neoformans and decreased toxicity towards mammalian cells. For example, the selectivity ratio for C. neoformans over mammalian fibroblasts was improved from 8 for AEC5 to 37 for β-5.Graphical abstractGraphical abstract for this article
       
  • 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based Fibrates as Potential
           Hypolipidemic and Hepatoprotective Agents
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Zi-Zhang Chen, Yun-Dong Xie, Li-Hua Shao, Qiu-Tang Wang, Yan-Hong Xu, Xiao-Li Bian Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1, 2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic and pancreatic tissues compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of curcumin-based fluorescent probes to
           detect Aβ fibrils
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Taki Sato, Mayumi Hotsumi, Koki Makabe, Hiroyuki Konno Amyloid β fibrillation is an early event in Alzheimer’s disease, so its detection is important to understand its roles in Alzheimer’s disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid β fibril activity in Alzheimer’s disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid β fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid β fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid β fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer’s disease.Graphical abstractGraphical abstract for this article
       
  • Structure-Activity Relationships of Pyrazole-4-carbodithioates as
           Antibacterials against Methicillin−Resistant Staphylococcus aureus
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hiwa Majed, Tatiana Johnston, Celine Kelso, Enrico Monachino, Slobodan Jergic, Nicholas E. Dixon, Eleftherios Mylonakis, Michael J. Kelso Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5−64 μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents.Graphical abstractGraphical abstract for this article
       
  • Discovery of vanadium complexes bearing tridentate shiff base ligands as
           novel LSD1 inhibitors
    • Abstract: Publication date: Available online 3 October 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ling-Pan Lu, Jin-Hai Liu, Shi-Hong Cen, Ya-Ling Jiang, Guo-Qiang Hu Lysine specific demethylase (LSD1) plays a pivotal role in epigenetic modulation of gene expression. Abberrant expression of LSD1 was associated with the progress and oncogenesis of multiple human cancers. Herein, we report the preliminary anti-LSD1 evaluation of the synthetic vanadium (V) complexes. Among them, complex 2 showed a moderate inhibitory effect against LSD1 with IC50 value of 19.0 μM, as well as good selectivity over MAO-A/B. Complex 2 is the first vanadium based LSD1 inhibitor, which provides a novel scaffold for the development of LSD1 inhibitor.Graphical abstractGraphical abstract for this article
       
  • Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent
           and selective ALK2 inhibitors
    • Abstract: Publication date: Available online 6 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jian-kang Jiang, Xiuli Huang, Khalida Shamim, Paresma R. Patel, Arthur Lee, Amy Q. Wang, Kimloan Nguyen, Gregory Tawa, Gregory D. Cuny, Paul B. Yu, Wei Zheng, Xin Xu, Philip Sanderson, Wenwei Huang The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.Graphical abstractGraphical abstract for this article
       
  • (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as
           tubulin polymerization inhibitors: Structure-based bioisosterism design,
           synthesis, biological evaluation, molecular docking and in silico ADME
           prediction
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Guangcheng Wang, Zhiyun Peng, Shanshan Peng, Jie Qiu, Yongjun Li, Yanyu Lan A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26–0.61 μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0.077– 7.44 μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC50 value of 0.9 µM, with ten folds more active than colchicine (IC50 = 9 μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Chemical space screening around Phe3 in opioid peptides:
           Modulating µ versus δ agonism by Suzuki-Miyaura cross-couplings”
           [Bioorg. Med. Chem. Lett. 28(13) (2018) 2320–2323]
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tom Willemse, Emilie Eiselt, Karlijn Hollanders, Wim Schepens, Herman W.T. van Vlijmen, Nga N. Chung, Véronique Blais, Brian Holleran, Jean-Michel Longpré, Peter W. Schiller, Bert U.W. Maes, Philippe Sarret, Louis Gendron, Steven Ballet
       
  • Synthesis and antiproliferative activities of novel quartenary ammonium
           spinosyn derivatives
    • Abstract: Publication date: Available online 5 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Da-You Ma, Long-Long Wang, Qin Lai, Kun-Jian Peng, Xuan Li, Zeng-Xia Li, Li-Jun Liu, Zhi-Yong Luo, Su-You Liu In order to enhance the mitochondria-targeting ability of spinosad. A series of quartenary ammonium spinosyn derivatives was designed and synthesized. Some of the derivatives displayed greatly enhanced antiproliferative ability towards tested human cancer cell lines. The structure activity relationship study indicated that lipophilicity has a great influence on the antiproliferative effects of these derivatives. The most active compound 11d exhibited remarkably enhanced OXPHS inhibition and apoptosis inducing ability than spinosyn A.Graphical abstractGraphical abstract for this article
       
  • Identification of inhibitors of the E. coli chaperone SurA using in silico
           and in vitro techniques
    • Abstract: Publication date: Available online 29 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Eric W. Bell, Erica J. Zheng, Lisa M. Ryno SurA is a gram-negative, periplasmic chaperone protein involved in the proper folding of outer membrane porins (OMPs), which protect bacteria against toxins in the extracellular environment by selectively regulating the passage of nutrients into the cell. Previous studies demonstrated that deletion of SurA renders bacteria more sensitive to toxins that compromise the integrity of the outer membrane. Inhibitors of SurA will perturb the folding of OMPs, leading to disruption of the outer membrane barrier and making the cell more vulnerable to toxic insults. The discovery of novel SurA inhibitors is therefore of great importance for developing alternative strategies to overcome antibiotic resistance. Our laboratory has screened over 10,000,000 compounds in silico by computationally docking these compounds onto the crystal structure of SurA. Through this screen and a screen of fragment compounds (molecular weight < 250 g/mol), we found twelve commercially readily available candidate compounds that bind to the putative client binding site of SurA. We confirmed binding to SurA by developing and employing a competitive fluorescence anisotropy-based binding assay. Our results show that one of these compounds, Fmoc- β -(2-quinolyl)-D-alanine, binds the client binding site with high micromolar affinity. Using this compound as a lead, we also discovered that Fmoc-L-tryptophan and Fmoc-L-phenylalanine, but not Fmoc-L-tyrosine, bind SurA with similar micromolar affinity. To our knowledge, this is the first report of a competitive fluorescence anisotropy assay developed for the identification of inhibitors of the chaperone SurA, and the identification of three small molecules that bind SurA at its client binding site.Graphical abstractSchematic of how the results from the ZINC12 Drugs Now library were processed.Graphical abstract for this article
       
  • Discovery of a Potent, Low-Absorbable Sodium-Dependent Glucose
           Cotransporter 1 (SGLT1) Inhibitor (TP0438836) for the Treatment of Type 2
           Diabetes
    • Abstract: Publication date: Available online 29 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shoichi Kuroda, Yohei Kobashi, Takahiro Oi, Hideaki Amada, Lisa Okumura-Kitajima, Fusayo Io, Koji Yamamto, Hiroyuki Kakinuma The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Design and synthesis of novel thiadiazole-thiazolone
           hybrids as potential inhibitors of the human mitotic kinesin Eg5 [Bioorg
           Med Chem Lett 28 (17) (2018) 2930–2938]”
    • Abstract: Publication date: Available online 29 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Samukelisiwe Pretty Khathi, Balakumar Chandrasekaran, Sivanandhan Karunanidhi, Chuin Lean Tham, Frank Kozielski, Nisar Sayyad, Rajshekhar Karpoormath
       
  • Novel KV7 ion channel openers for the treatment of epilepsy and
           implications for detrusor tissue contraction
    • Abstract: Publication date: Available online 29 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mark A. Seefeld, Hong Lin, Joerg Holenz, Dave Downie, Brian Donovan, Tingting Fu, Kishore Pasikanti, Wei Zhen, Matthew Cato, Khuram W. Chaudhary, Pat Brady, Tania Bakshi, Dwight Morrow, Sridharan Rajagopal, Swapan Kumar Samanta, Naveena Madhyastha, Bharathi Mohan Kuppusamy, Robert W. Dougherty, Ravi Bhamidipati, Zainuddin Mohd Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.2009 Elsevier Ltd. All rights reserved.Graphical abstractGraphical abstract for this article
       
  • Discovery of heterocyclic replacements for the coumarin core of
           anti-tubercular FadD32 inhibitors
    • Abstract: Publication date: Available online 29 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Chao Fang, Katie K. Lee, Raymond Nietupski, Robert H. Bates, Raquel Fernandez-Menendez, Eva Maria Lopez-Roman, Laura Guijarro-Lopez, Yunxing Yin, Zuozhong Peng, James E. Gomez, Stewart Fisher, David Barros-Aguirre, Brian K. Hubbard, Michael H. Serrano-Wu, Deborah T. Hung Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.Graphical abstractGraphical abstract for this article
       
  • Discovery of a novel series of pyridine and pyrimidine carboxamides as
           potent and selective covalent inhibitors of Btk
    • Abstract: Publication date: Available online 27 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Richard Caldwell, Lesley Liu-Bujalski, Hui Qiu, Igor Mochalkin, Reinaldo Jones, Constantin Neagu, Andreas Goutopoulos, Roland Grenningloh, Theresa Johnson, Brian Sherer, Anna Gardberg, Ariele Viacava Follis, Federica Morandi, Jared HeadGraphical abstractGraphical abstract for this article
       
  • Discovery of a potent orally bioavailable retinoic acid receptor-related
           orphan receptor-gamma-t (RORγt) inhibitor, S18-000003
    • Abstract: Publication date: Available online 27 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yoshikazu Sasaki, Masahide Odan, Shiho Yamamoto, Shiro Kida, Masaya Shimizu, Takayo Haruna, Azumi Ueyama, Ayahisa Watanabe, Takayuki Okuno The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure–activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.Graphical abstractGraphical abstract for this article
       
  • Identification of steroidal derivatives inhibiting the transformations of
           allopregnanolone and estradiol by 17β-hydroxysteroid dehydrogenase type
           10
    • Abstract: Publication date: Available online 26 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Sophie Boutin, Jenny Roy, René Maltais, Wael Alata, Frédéric Calon, Donald Poirier 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known for its potential role in Alzheimer’s Disease (AD). 17β-HSD10, by its oxidative activity, could decrease the concentration of two important neurosteroids, allopregnanolone (ALLOP) and 17β-estradiol (E2), respectively preventing their neurogenesis and neuroprotective effects. Since the inhibition of 17β-HSD10 could lead to a new treatment for AD, we developed two biological assays using labeled ALLOP or E2 as substrates to measure the inhibitory activity of compounds against pure 17β-HSD10 protein. After the optimization of different parameters (time, concentration of enzyme, substrate and cofactor), analogs of the first reported steroidal inhibitor of 17β-HSD10 in intact cells were screened to determine their inhibitory potency for the ALLOP or the E2 oxidation. One compound, androstane derivative 5, possesses the best dual inhibition against both transformations (ALLOP, IC50 = 235 μM and E2, IC50 = 610 μM). Some compounds are dual inhibitors to a lesser extent, and others seem selective for one of the transformations in particular. By developing two reliable assays and by identifying a first generation of steroidal inhibitors of pure 17β-HSD10, this preliminary study opens the door to new and more potent inhibitors.Graphical abstractGraphical abstract for this article
       
  • Radiosynthesis and evaluation of a fluorine-18 labeled radioligand
           targeting vesicular acetylcholine transporter
    • Abstract: Publication date: Available online 24 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Xuyi Yue, Zonghua Luo, Hui Liu, Kota Kaneshige, Stanley M. Parsons, Joel S. Perlmutter, Zhude Tu Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (±)-5-OH-VAT is potent (Ki = 4.64 ± 0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ1 and σ2 receptor) with favorable hydrophilicity with LogD value of 1.78, although (-)-5-OH-VAT originally serves as the radiolabeling precursor of (-)-[18F]VAT, a promising VAChT radiotracer with logD value of 2.56. To evaluate (-)-5-OH-[18F]VAT as a radiotracer for VAChT, we performed in vitro assay to determine the potency of the minus enantiomer (-)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (-)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (-)-5-OH-[18F]VAT was explored using three strategies. (-)-5-OH-[18F]VAT was achieved with a good yield (24 ± 6%) and high molar activity (∼ 37 GBq/µmol, at the end of synthesis) using a microwave assist two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (-)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (-)-5-OH-[18F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [18F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measure the VAChT level in the brain.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation and molecular modeling of a novel series
           of fused 1,2,3-triazoles as potential anti-coronavirus agents
    • Abstract: Publication date: Available online 22 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Konstantina Karypidou, Sergio R. Ribone, Mario A. Quevedo, Leentje Persoons, Christophe Pannecouque, Christine Helsen, Frank Claessens, Wim Dehaen Synthesis and biological evaluation of a novel library of fused 1,2,3-triazole derivatives are described. The in-house developed multicomponent reaction based on commercially available starting materials was applied and broad biological screening against various viruses was performed, showing promising antiviral properties for compounds 14d, 14n, 14q, 18f and 18i against human coronavirus 229E. Further in silico studies identified the key molecular interactions between those compounds and the 3-chymotrypsin-like protease, which is essential to the intracellular replication of the virus, supporting the hypothesis that the protease is the target molecule of the potential antiviral derivatives.Graphical abstractGraphical abstract for this article
       
  • Clickable Photoaffinity Ligands for the Human Serotonin Transporter Based
           on the Selective Serotonin Reuptake Inhibitor (S)-Citalopram
    • Abstract: Publication date: Available online 22 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nageswari Yarravarapu, Laura Geffert, Christopher K. Surratt, Michael Cascio, David J. Lapinsky To date, the development of photoaffinity ligands targeting the human serotonin transporter (hSERT), a key protein involved in disease states such as depression and anxiety, have been radioisotope-based (i.e., 3H or 125I). This letter instead highlights three derivatives of the selective serotonin reuptake inhibitor (SSRI) (S)-citalopram that were rationally designed and synthesized to contain a photoreactive benzophenone or an aryl azide for protein target capture via photoaffinity labeling and a terminal alkyne or an aliphatic azide for click chemistry-based proteomics. Specifically, clickable benzophenone-based (S)-citalopram photoprobe 6 (hSERT Ki = 0.16 nM) displayed 11-fold higher binding affinity at hSERT when compared to (S)-citalopram (hSERT Ki = 1.77 nM), and was subsequently shown to successfully undergo tandem photoaffinity labeling-biorthogonal conjugation using purified hSERT. Given clickable photoprobes can be used for various applications depending on which reporter is attached by click chemistry subsequent to photoaffinity labeling, photoprobe 6 is expected to find value in structure-function studies and other research applications involving hSERT (e.g., imaging).Graphical abstractGraphical abstract for this article
       
  • FITC-labeled D-glucose analog is suitable as a probe for detecting
           insulin-dependent glucose uptake
    • Abstract: Publication date: Available online 21 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lin Su, Rui Wu, Xinrou Chen, Wei Hou, Benfang Helen Ruan The detection of the insulin-dependent glucose uptake is a vital part in the research of diabetes. To establish a sensitive assay for measuring glucose uptake in living cells, we synthesized a FITC linked D-glucosamine 2 as a probe. 2 was obtained by the reaction of commercially available D-glucosamine hydrochloride and FITC and was determined as a single anomeric form by 1H NMR and13C NMR. 2 exhibited good water solubility and stability. An uptake assay in HepG2 cells with or without insulin demonstrated that FITC showed strong cellular uptake, whereas uptake of 2 is much less but is insulin dependent. This suggests that 2 is specifically transported into cells through a receptor that is regulated by insulin and has potential application in screening of compounds or genes that regulate the insulin-dependence in cell-based assays.Graphical abstractGraphical abstract for this article
       
  • Efficient optimization of pyrazolo[3,4-d]pyrimidines derivatives as c-Src
           kinase inhibitors in neuroblastoma treatment
    • Abstract: Publication date: Available online 20 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Alessio Molinari, Anna Lucia Fallacara, Salvatore Di Maria, Claudio Zamperini, Federica Poggialini, Francesca Musumeci, Silvia Schenone, Adriano Angelucci, Alessandro Colapietro, Emmanuele Crespan, Miroslava Kissova, Giovanni Maga, Maurizio Botta The proto-oncogene c-Src is a non-receptor tyrosine kinase which is involved in the regulation of many cellular processes, such as differentiation, adhesion and survival. c-Src hyperactivation has been detected in many tumors, including neuroblastoma (NB), one of the major causes of death from neoplasia in infancy. We already reported a large family of pyrazolo[3,4-d]pyrimidines active as c-Src inhibitors. Interestingly, some of these derivatives resulted also active on SH-SY5Y NB cell line. Herein, starting from our previous Free Energy Perturbation/Monte Carlo calculations, we report an optimization study which led to the identification of a new series of derivatives endowed with nanomolar Ki values against c-Src, interesting antiproliferative activity on SH-SY5Y cells and a suitable ADME profile.Graphical abstractGraphical abstract for this article
       
  • Dithiocarbamates: Efficient metallo-β-lactamase inhibitors with good
           antibacterial activity when combined with meropenem
    • Abstract: Publication date: Available online 20 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ming-Ming Wang, Wen-Chao Chu, Yi Yang, Qian-Qian Yang, Shang-Shang Qin, En Zhang The activity of β-lactam antibiotics is compromised by metallo-β-lactamases (MBLs). Herein, a series of dithiocarbamate derivatives were designed and synthesized. Their antibacterial activities were tested in combination with meropenem (MEM) against several MBL (NDM and IMP type)-producing clinical isolates. Clinical isolates harboring NDM-1 and IMP-4 became susceptible to MEM when it was combined with dithiocarbamate compounds 4a, 4b or 4f synthesized in this work. Compounds 4a and 4b increased the effectiveness of MEM by up to 2560 times against strains. In vitro bactericidal dynamics tests showed that bacteria died within 24 h when they were treated with compound 4f + MEM. Compounds 4a, 4b and 4f were non-hemolytic and exhibited low toxicity toward HeLa cells in vitro. These data show that compounds containing dithiocarbamate functional group may be helpful in the development of MBL inhibitors.Graphical abstractGraphical abstract for this article
       
  • Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with
           improved selectivity and antiproliferative activity: synthesis and
           structure-activity relationships
    • Abstract: Publication date: Available online 19 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shao-Lin Zhang, Zheng Yang, Xiaohui Hu, Kin Yip Tam Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Biological Evaluation of
           (2S,3R,4R,5S,6R)-5-Fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols
           as Potent and Orally Active SGLT Dual Inhibitors
    • Abstract: Publication date: Available online 19 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Guozhang Xu, Michael D. Gaul, Gee-Hong Kuo, Fuyong Du, June Zhi Xu, Nathaniel Wallace, Simon Hinke, Thomas Kirchner, Jose Silva, Norman D. Huebert, Seunghun Lee, William Murray, Yin Liang, Keith Demarest A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.Graphical abstractGraphical abstract for this article
       
  • Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for
           the topical treatment of inflammatory skin disease
    • Abstract: Publication date: Available online 18 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Michael D. Barker, John Liddle, Francis L. Atkinson, David Matthew Wilson, Marion C. Dickson, Cesar Ramirez-Molina, Huw Lewis, Rob P. Davis, Donald O. Somers, Margarete Neu, Emma Jones, Robert Watson The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.Graphical abstractGraphical abstract for this article
       
  • Ferrocene-Based Inhibitors of Hepatitis C Virus Replication that Target
           NS5A with Low Picomolar In Vitro Antiviral Activity
    • Abstract: Publication date: Available online 18 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Venkat R. Gadhachanda, Kyle J. Eastman, Qiuping Wang, Avinash S. Phadke, Dharaben Patel, Wengang Yang, Christopher W. Marlor, Milind Deshpande, Mingjun Huang, Jason A. Wiles An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1’-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.Graphical abstractGraphical abstract for this article
       
  • 1,2,3-Triazole fused with pyridine / pyrimidine as new template for
           antimicrobial agents: Regioselective synthesis and identification of
           potent N-heteroarenes
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nagaraju Marepu, Sunandamma Yeturu, Manojit Pal The 1,2,3-triazole ring fused with pyridine / pyrimidine was explored as new template for the identification of potential antimicrobial agents. The regioselective synthesis of these pre-designed N-heteroarenes was achieved via exploring the application of Buchwald’s strategy (i.e. C-N bond formation / reduction / diazotization / cyclization sequence) to the N-heteroarene system. Two of them showed promising antibacterial (comparable to streptomycin) and several showed potent antifungal (comparable to mancozeb) activities.Graphical abstractGraphical abstract for this article
       
  • Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate
           ester analogs of the acetaminophen derivative SCP-1
    • Abstract: Publication date: Available online 17 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Madhurima Das, Surjyadipta Bhattacharjee, Frank R. Fronczek, Nicolas G. Bazan, Mark L. Trudell A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen.Graphical abstractGraphical abstract for this article
       
  • Optimization of the efflux ratio and permeability of covalent irreversible
           BTK inhibitors
    • Abstract: Publication date: Available online 15 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hui Qiu, Lesley Liu-Bujalski, Richard D Caldwell, Ariele Viacava Follis, Anna Gardberg, Andreas Goutopoulos, Roland Grenningloh, Jared Head, Theresa Johnson, Christopher CV Jones, Reinaldo Jones, Igor Mochalkin, Federica Morandi, Constantin Neagu, Justin Potnick, Brian Sherer Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.Graphical abstractGraphical abstract for this article
       
  • Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored
           biotinylated camptothecin derivative
    • Abstract: Publication date: Available online 15 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Olga Minenkova, Loredana Vesci, Rita De Santis, Daniela Santapaola, Raffaella Cincinelli, Loana Musso, Sabrina Dallavalle, Giuseppe Giannini Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors.Graphical abstractAvidinOX, an oxidated form of avidin, provides stable fixation of biotinylated molecules in tissues. Here we investigated the possibility to hold a novel biotinylated gimatecan-derived camptothecin in AvidinOX-treated sites. When the biotinylate camptothecin ST8161AA1 was injected at suboptimal doses, in combination with AvidinOX, in mice bearing human tumors xenografted, a higher growth inhibition was observed compared to when it was administered alone.Graphical abstract for this article
       
  • Methyl-Containing Pharmaceuticals: Methylation in Drug Design
    • Abstract: Publication date: Available online 14 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shaoyi Sun, Jianmin Fu The importance of methyl groups in modulating biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of biologically active molecules is highlighted. The information compiled from selected beneficial cases, focuses mostly on marketed drugs and clinical candidates, and indicates that the methylation strategy has been successful in drug design.Graphical abstractGraphical abstract for this article
       
  • Supramolecular complexes for Nanomedicine
    • Abstract: Publication date: Available online 13 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Chiara M.A. Gangemi, Roberta Puglisi, Andrea Pappalardo, Giuseppe Trusso Sfrazzetto Host-guest interactions studied in supramolecular chemistry have been inspired by interactions between enzymes and substrates. Furthermore, most of the interactions involved in the cells are based on non-covalent bonds between two or more molecules. The common aspects between supramolecular chemistry and medicine have led to the development of a “new” area called “supramolecular medicine”, in which non-covalent interactions and self-assembly processes are applied within several medical fields.The object of this Digest is to offer an account of how some macrocyclic hosts (e.g. cucurbiturils, cyclodextrins, pillararenes and calixarenes) are employed in supramolecular medicine creating new supramolecular hydrogels used as biomaterials for human tissue in regenerative medicine, and a diagnostic instrument, in-vitro and in-vivo, for the detection of diseases, as well as for the investigation of cell morphology.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and evaluation of carboxyl-modified Oseltamivir
           derivatives with improved lipophilicity as neuraminidase inhibitors
    • Abstract: Publication date: Available online 12 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Boyu Wang, Kuanglei Wang, Peipei Meng, Yaping Hu, Fei Yang, Kemin Liu, Zaiqiang Lei, Binfeng Chen, Yongshou Tian In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50 = 1.30 ± 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (Log D = -0.12) is more lipophilic than oseltamivir carboxylate (Log D = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.Graphical abstractGraphical abstract for this article
       
  • Unexpected AChE inhibitory activity of (2E)α,β
           -unsaturated fatty acids
    • Abstract: Publication date: Available online 11 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Anne Loesche, Jana Wiemann, Zayan Al Halabi, Julia Karasch, Wolfgang Sippl, René Csuk A small library of (E) α,β -unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman’s assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50 = 4.3 to 12.8 μM with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants Ki = 1.51 ± 0.09 μM and Ki’= 7.15 ± 0.55 μM. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.Graphical abstractGraphical abstract for this article
       
  • Antimicrobial 1,3,4-trisubstituted-1,2,3-triazolium salts
    • Abstract: Publication date: Available online 10 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): James T. Fletcher, Jill M. Sobczyk, Sarah C. Gwazdacz, Aaron J. Blanck A series of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts were prepared by efficient two-step sequences of azide-alkyne cycloaddition and benzylic substitution. The antimicrobial activity of each triazolium salt and correlating triazole precursor was evaluated using a minimum inhibitory concentration (MIC) assay. MIC activities as low as 1 µM against Gram-positive bacteria, 8 µM against Gram-negative bacteria and 4 µM against fungi were observed for salt analogs, while neutral triazoles were inactive. Analogs representing selective and broad-spectrum antimicrobial activity were each identified. MIC structure-activity relationships observed within this motif indicate that the presence of cationic charge and balance of overall hydrophobicity are strongly impactful, while benzyl vs. aryl substituent identity and variation of substituent regiochemistry are not.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antibacterial activity of novel
           3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime
           clarithromycin derivatives
    • Abstract: Publication date: Available online 10 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yinhui Qin, Shengsheng Qiang, Shengli Ji, Zhiyang Liu, Chaoyu Hu, Shutao Ma A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125 µg/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4 µg/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8 µg/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.Graphical abstractGraphical abstract for this article
       
  • Synthesis of Novel Mono and Bis Nitric Oxide Donors with High
           Cytocompatibility and Release Activity
    • Abstract: Publication date: Available online 8 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tanya Sahyoun, Caroline Gaucher, Yi Zhou, Naïm Ouaini, Raphaël Schneider, Axelle Arrault Four compounds bearing amidoxime functions were synthetized: (1) 2a-b bearing an aromatic amidoxime function, (2) 2c bearing an aliphatic amidoxime function, and (3) 2d bearing aromatic and aliphatic amidoximes functions. The ability of these compounds to release NO was evaluated in vitro using the oxidative metabolism of cytochrome P450 from rat liver microsomes. Results obtained demonstrate that all amidoximes were able to release NO with a highest amount of NO produced by the 2a aromatic amidoxime. Moreover, all amidoximes exhibit cytocompatibility with human aorta smooth muscle cells. Using intracellular S-nitrosothiol formation as a marker of NO bioavailability, compounds 2a-c were demonstrated to deliver a higher amount of NO in the intracellular environment than the reference. Considering that the concentration of the bis-amidoxime 2d was two times lower that than of 2a and 2b, we can assume that 2d is the most potent molecule among the tested compounds for NO release.Graphical abstractGraphical abstract for this article
       
  • Discovery of DS42450411 as a potent orally active hepcidin production
           
    • Abstract: Publication date: Available online 8 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Takeshi Fukuda, Takashi Ishiyama, Takahiro Katagiri, Kenjiro Ueda, Sumie Muramatsu, Masami Hashimoto, Anri Aki, Daichi Baba, Kengo Watanabe, Naoki Tanaka Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological activities of novel pyrazolomatrine derivatives
    • Abstract: Publication date: Available online 6 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Wenlong Kong, Yinhe Bao, Qianjun Ma, Hui Xu In continuation of our program aimed at the development of new natural product-based pesticides, a series of novel pyrazolomatrine derivatives were prepared by structural modifications of matrine, isolated as a quinolizidine alkaloid from the roots of Sophora flave. Their structures were confirmed by 1H NMR, HRMS, etc. Moreover, the steric structures of three compounds were determined by single-crystal X-ray diffraction. Among all derivatives, 19-(naphthyl-2-oyl)pyrazolomatrine (5y) showed 3.13-fold more potent acaricidal activity than its precusor matrine against Tetranychus cinnabarinus; 19-(4-methylbenzoyl)pyrazolomatrine (5j) and 19-(3,5-dimethylbenzoyl)pyrazolomatrine (5k) displayed the promising aphicidal activity against Aphis citricola van der. Their structure-activity relationships were also observed.Graphical abstractGraphical abstract for this article
       
  • Inhibitor for FcεRI expression on mast cell from Verbasucum
           thapsus
    L.
    • Abstract: Publication date: Available online 6 September 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Satoru Tamura, Kunichika Yoshihira, Tomikazu Kawano, Nobutoshi Murakami We found out 2',3'-dihydroxypuberulin from South American medicinal plant, V. thapsus L., as a candidate of an anti-allergic lead which inhibits the expression of high-affinity receptor of IgE (FcεRI) on the surface of mast cells. Furthermore, the analysis of structure-activity relationship by using synthesized 2',3'-dihydroxypuberulin analogs revealed that both hydroxy groups in the side chain and both of methyl moieties on phenolic hydroxy groups were crucial for potent activity, but absolute configuration of C-3' position wasn't. The active principle, 2',3'-dihydroxypuberulin, was disclosed to down-regulate the mRNA level of β-chain of FcεRI, different from previous reported active natural product reducing γ-chain level.Graphical abstractGraphical abstract for this article
       
 
 
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