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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28633899/discovery-of-bms-961955-an-allosteric-inhibitor-of-the-hepatitis-c-virus-ns5b-polymerase
#1
Barbara Zhizhen Zheng, Stanley V D'Andrea, Umesh Hanumegowda, Jay O Knipe, Kathy Mosure, Xiaoliang Zhuo, Julie A Lemm, Mengping Liu, Karen L Rigat, Ying-Kai Wang, Hua Fang, Chris Poronsky, Jingfang Cutrone, Dauh-Rurng Wu, Pirama Nayagam Arunachalam, T J Balapragalathan, Arunachalam Arumugam, Arvind Mathur, Nicholas A Meanwell, Min Gao, Susan B Roberts, John F Kadow
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency(TM).
June 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610984/sar-and-characterization-of-non-substrate-isoindoline-urea-inhibitors-of-nicotinamide-phosphoribosyltransferase-nampt
#2
Michael L Curtin, H Robin Heyman, Richard F Clark, Bryan K Sorensen, George A Doherty, T Matthew Hansen, Robin R Frey, Kathy A Sarris, Ana L Aguirre, Anurupa Shrestha, Noah Tu, Kevin Woller, Marina A Pliushchev, Ramzi F Sweis, Min Cheng, Julie L Wilsbacher, Peter J Kovar, Jun Guo, Dong Cheng, Kenton L Longenecker, Diana Raich, Alla V Korepanova, Nirupama B Soni, Mikkel A Algire, Paul L Richardson, Violeta L Marin, Ilaria Badagnani, Anil Vasudevan, F Greg Buchanan, David Maag, Gary G Chiang, Chris Tse, Michael R Michaelides
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed...
June 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610983/design-and-synthesis-of-a-novel-inhibitor-of-t-viride-chitinase-through-an-in-silico-target-fishing-protocol
#3
Giorgio Maccari, Davide Deodato, Diego Fiorucci, Francesco Orofino, Giuseppina I Truglio, Carolina Pasero, Riccardo Martini, Filomena De Luca, Jean-Denis Docquier, Maurizio Botta
In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank...
June 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633898/2-chlorophenyl-substituted-benzofuro-3-2-b-pyridines-with-enhanced-topoisomerase-inhibitory-activity-the-role-of-the-chlorine-substituent
#4
Til Bahadur Thapa Magar, Tara Man Kadayat, Hwa-Jong Lee, Seojeong Park, Ganesh Bist, Aarajana Shrestha, Youngjoo Kwon, Eung-Seok Lee
A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17-19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.
June 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28624142/anti-diabetic-xanthones-from-the-bark-of-garcinia-xanthochymus
#5
Chi N Nguyen, Binh T D Trinh, Toan B Tran, Le-Thu T Nguyen, Anna K Jäger, Lien-Hoa D Nguyen
An ethyl acetate extract the bark of Garcinia xanthochymus exhibited strong inhibition towards α-glucosidase and PTP1B with IC50 values of 0.3±0.1μg/mL and 2.3±0.4μg/mL, respectively. Chemical constituents of the extract were therefore examined, and two new compounds, xanthochymusxanthones A (1) and B (2), along with ten known xanthones (3-12), were isolated. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Inhibitory activity of the isolated compounds was then tested, and subelliptenone F (12) showed significant effect towards α-glucosidase with IC50 value of 4...
June 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28625363/design-synthesis-and-biological-evaluation-of-novel-indolin-2-ones-as-potent-anticancer-compounds
#6
Andong Zhou, Lei Yan, Fangfang Lai, Xiaoguang Chen, Masuo Goto, Kuo-Hsiung Lee, Zhiyan Xiao
The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c...
June 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633896/design-synthesis-and-biological-evaluation-of-novel-3h-imidazole-4-5-b-pyridine-derivatives-as-selective-mtor-inhibitors
#7
Lingzhi Zhang, Tantan Bu, Xiaobo Bao, Tingting Liang, Yiran Ge, Yungen Xu, Qihua Zhu
A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kα. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780).
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633895/synthesis-of-meon-neoglycosides-of-digoxigenin-with-6-deoxy-and-2-6-dideoxy-d-glucose-derivatives-and-their-anticancer-activity
#8
Dong-Dong Wang, Xiao-San Li, Yu-Zhou Bao, Jie Liu, Xiao-Kun Zhang, Xin-Sheng Yao, Xue-Long Sun, Jin-Shan Tang
Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital for their anticancer effects. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and get more potent anticancer agents, a series of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten 6-deoxy- and 2,6-dideoxy-d-glucopyranosyl donors were synthesized starting from methyl α-d-glucopyranoside and 2-deoxy-d-glucose. Meanwhile, the digoxigenin was obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633894/synthesis-and-antibacterial-activity-of-5-methylphenanthridium-derivatives-as-ftsz-inhibitors
#9
Fang Liu, Henrietta Venter, Fangchao Bi, Susan J Semple, Jingru Liu, Chaobin Jin, Shutao Ma
5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28629595/a-novel-intestinal-restricted-fxr-agonist
#10
Hong Wang, Zhou Zhao, Jiyu Zhou, Yitong Guo, Guangji Wang, Haiping Hao, Xiaowei Xu
In this study, a new intestinal-restricted FXR agonist named fexaramine-3 (Fex-3) was developed and investigated both in vitro and in vivo. Fex-3 could selectively activate intestinal FXR and promote the expression of BSEP and SHP while suppressing CYP7A1 which is involved in bile acids syntheses better than the reported intestinal-restricted FXR agonist fexaramine (Fex). We demonstrated that Fex-3 targeted on FXR in ileum and has better selectivity than Fex. And the study of utilizing Fex-3 to reduce obesity was undergoing...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28624143/a-small-molecule-screen-identifies-the-antitrypanosomal-agent-suramin-and-analogues-nf023-and-nf449-as-inhibitors-of-stat5a-b
#11
Angela Berg, Thorsten Berg
The transcription factor STAT5a is a potential target for tumor therapy. We present a fluorescence polarization-based, high-throughput screen of chemical libraries containing natural products and known bioactive molecules, for the identification of small-molecule inhibitors of the STAT5a SH2 domain. This screen identified suramin, a drug used to treat African trypanosomiasis, and its analogues NF023 and NF449 as inhibitors of the SH2 domains of STAT5a/b. Our data extend the known in vitro targets of suramin and analogues to include members of the STAT protein family...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28619537/synthesis-and-biological-evaluation-of-caffeic-acid-derivatives-as-potent-inhibitors-of-%C3%AE-msh-stimulated-melanogenesis
#12
Hyeju Jo, Minho Choi, Jaeuk Sim, Mayavan Viji, Siyuan Li, Young Hee Lee, Youngsoo Kim, Seung-Yong Seo, Yuanyuan Zhou, Kiho Lee, Wun-Jae Kim, Jin Tae Hong, Heesoon Lee, Jae-Kyung Jung
We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28615134/synthesis-and-biological-evaluation-of-5-fatty-acylamido-1-3-4-thiadiazole-2-thioglycosides
#13
Srikanth Vudhgiri, Dhevendar Koude, Dileep Kumar Veeragoni, Sunil Misra, R B N Prasad, Ram Chandra Reddy Jala
In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a-4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a-4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610985/design-synthesis-and-herbicidal-activity-study-of-aryl-2-6-disubstituted-sulfonylureas-as-potent-acetohydroxyacid-synthase-inhibitors
#14
Wei Wei, Shaa Zhou, Dandan Cheng, Yuxin Li, Jingbo Liu, Yongtao Xie, Yonghong Li, Zhengming Li
A series of sulfonylurea derivatives containing a 2,6-disubstituted aryl moiety were designed, synthesized and evaluated for their herbicidal activities. Most of these compounds showed excellent inhibitory rates against both monocotyledonous and dicotyledonous weeds, especially 10a, 10h and 10i. They exhibited equivalent or superior herbicidal efficiency than commercial chlorsulfuron at the dosage of 15g/ha and the preliminary SAR was summarized. In order to illuminate the molecular mechanism of several potent compounds, their apparent inhibition constant (Ki(app)) of Arabidopsis thaliana acetohydroxyacid synthase (AHAS) were determined and the results confirmed that these compounds were all potent AHAS inhibitors...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610982/synthesis-potential-anti-inflammatory-and-analgesic-activities-study-of-s-n-substituted-1-phenyl-3-4-dihydroisoquinoline-2-1h-carboxamides
#15
Li-Ping Guan, Ya-Nan Xia, Qing-Hao Jin, Bing-Yu Liu, Si-Hong Wang
A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610980/synthetic-ligand-promotes-gene-expression-by-affecting-gc-sequence-in-promoter
#16
Saki Matsumoto, Kei Iida, Asako Murata, Masatsugu Denawa, Masatoshi Hagiwara, Kazuhiko Nakatani
A naphthyridine carbamate tetramer (NCT8) is a synthetic compound, which selectively binds to nucleic acids containing CGG/CGG sequence. Although NCT8 is a promising compound for a wide range of DNA and RNA based biotechnology such as modulation of specific gene expression, little is known about its behavior in human cells. In the present study, we investigated the changes induced in gene expression by NCT8. Genes differentially expressed in the presence of NCT8 in HeLa cells were identified by whole-transcriptome analysis...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610977/novel-3-fluoro-6-methoxyquinoline-derivatives-as-inhibitors-of-bacterial-dna-gyrase-and-topoisomerase-iv
#17
Mark J Mitton-Fry, Steven J Brickner, Judith C Hamel, Rose Barham, Lori Brennan, Jeffrey M Casavant, Xiaoyuan Ding, Steven Finegan, Joel Hardink, Thuy Hoang, Michael D Huband, Meghan Maloney, Anthony Marfat, Sandra P McCurdy, Dale McLeod, Chakrapani Subramanyam, Michael Plotkin, Usa Reilly, John Schafer, Gregory G Stone, Daniel P Uccello, Todd Wisialowski, Kwansik Yoon, Richard Zaniewski, Christopher Zook
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610976/dioscin-suppresses-tgf-%C3%AE-1-induced-epithelial-mesenchymal-transition-and-suppresses-a549-lung-cancer-migration-and-invasion
#18
Won-Chul Lim, Hyunhee Kim, Young-Joo Kim, Kyung-Chul Choi, In Ho Lee, Ki Heon Lee, Mi Kyung Kim, Hyeonseok Ko
Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28610975/pna-monomers-fully-compatible-with-standard-fmoc-based-solid-phase-synthesis-of-pseudocomplementary-pna
#19
Toru Sugiyama, Genki Hasegawa, Chie Niikura, Keiko Kuwata, Yasutada Imamura, Yosuke Demizu, Masaaki Kurihara, Atsushi Kittaka
Here we report the synthesis of new PNA monomers for pseudocomplementary PNA (pcPNA) that are fully compatible with standard Fmoc chemistry. The thiocarbonyl group of the 2-thiouracil (sU) monomer was protected with the 4-methoxy-2-methybenzyl group (MMPM), while the exocyclic amino groups of diaminopurine (D) were protected with Boc groups. The newly synthesized monomers were incorporated into a 10-mer PNA oligomer using standard Fmoc chemistry for solid-phase synthesis. Oligomerization proceeded smoothly and the HPLC and MALDI-TOF MS analyses indicated that there was no remaining MMPM on the sU nucleobase...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28606761/inhibition-of-bromodomain-containing-protein-9-for-the-prevention-of-epigenetically-defined-drug-resistance
#20
Terry D Crawford, Steffan Vartanian, Alexandre Côté, Steve Bellon, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Eneida Pardo, F Anthony Romero, Peter Sandy, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Laura Zawadzke, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran, David Stokoe
Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
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