共查询到20条相似文献,搜索用时 31 毫秒
1.
Xiaoyan Zhang Nanjing Zhang Guangming Chen Anthony Turpoff Hongyu Ren James Takasugi Christie Morrill Jin Zhu Chunshi Li William Lennox Steven Paget Yalei Liu Neil Almstead F. George Njoroge Zhengxian Gu Takashi Komatsu Valerie Clausen Christine Espiritu Gary M. Karp 《Bioorganic & medicinal chemistry letters》2013,23(13):3947-3953
A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50 = 4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6 h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target. 相似文献
2.
Agustin Casimiro-Garcia Ronald J. Heemstra Christopher F. Bigge Jing Chen Fred A. Ciske Jo Ann Davis Teresa Ellis Nadia Esmaeil Declan Flynn Seungil Han Mehran Jalaie Jeffrey F. Ohren Noel A. Powell 《Bioorganic & medicinal chemistry letters》2013,23(3):767-772
Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC50 = 7 nM; PPARγ EC50 = 295 nM, 27% max) and good ADME properties. 相似文献
3.
《Bioorganic & medicinal chemistry》2014,22(3):986-996
Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki = 0.07 nM; MT2, Ki = 0.08 nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50 = 0.8 nM and Emax = 98%) and 6b (EC50 = 0.2 nM and Emax = 121%) exhibited good pharmacological profiles. 相似文献
4.
Anandarajan Thiyagarajan Mohammed T.A. Salim Tuniki Balaraju Chandralata Bal Masanori Baba Ashoke Sharon 《Bioorganic & medicinal chemistry letters》2012,22(24):7742-7747
The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure–activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement of the amino group. The ligand conformation, binding mode studies and drug like properties were major determinant for selection of molecules for final synthesis. The replacement of amino group with methyl restored the interactions with RNA-template (Tem 799) through bifurcated weak H-bond (C–H…O). This is an interesting finding observed from molecular modeling studies. It was found that 6c–e has anti-HCV activity (EC50 in 37–46 μM) while 6a, 6b and 6g were inactive. The compound 6f (EC50 28 μM) was the most active among the series however it also showed some cytotoxicity (CC50 52.8 μM). Except 6f, none of the compounds were found to be cytotoxic (CC50 > 100 μM). The present study discloses structure–based approach for novel anti-HCV lead discovery and opens a future scope of lead optimization. 相似文献
5.
Andreas Ritzén Rikke Sindet Morten Hentzer Nannette Svendsen Robbin M. Brodbeck Christoffer Bundgaard 《Bioorganic & medicinal chemistry letters》2009,19(12):3275-3278
This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC50 = 30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration. 相似文献
6.
Deena S. Lasheen Mohamed A.H. Ismail Dalal A. Abou El Ella Nasser S.M. Ismail Sameh Eid Susan Vleck Jeffrey S. Glenn Andrew G. Watts Khaled A.M. Abouzid 《Bioorganic & medicinal chemistry》2013,21(10):2742-2755
Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors. In vitro based studies were then performed to evaluate the efficacies of the inhibitors using Human hepatoma cells, with the vinyl sulfonate ester (10) in particular, found to have highly potent anti-HCV activity with an EC50 = 0.296 μM. Finally, molecular modeling studies were performed through docking of the synthesized compounds in the HCV NS3/4A protease active site to assess their binding modes with the enzyme and gain further insight into their structure–activity relationships. 相似文献
7.
《Bioorganic & medicinal chemistry》2016,24(11):2530-2543
N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(6):1581-1588
Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 = 3.3 μM, SI >30.3, 12b, EC50 = 3.5 μM, SI >28.6, 10l, EC50 = 3.9 μM, SI >25.6, 12o, EC50 = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents. 相似文献
9.
Iou-Jiun Kang Li-Wen Wang Teng-Kuang Yeh Chung-Chi Lee Yen-Chun Lee Sheng-Ju Hsu Yen-Shian Wu Jing-Chyi Wang Yu-Sheng Chao Andrew Yueh Jyh-Haur Chern 《Bioorganic & medicinal chemistry》2010,18(17):6414-6421
A series of novel conformationally-restricted thiourea analogs were designed, synthesized, and evaluated for their anti-HCV activity. Herein we report the synthesis, structure–activity relationships (SARs), and pharmacokinetic properties of this new class of thiourea compounds that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the fluorene compound 4b was found to possess the most potent activity (EC50 = 0.3 μM), lower cytotoxicity (CC50 > 50 μM), and significantly better pharmacokinetic properties compared to its corresponding fluorenone compound 4c. 相似文献
10.
Xianming Deng Sang Min Lim Jianming Zhang Nathanael S. Gray 《Bioorganic & medicinal chemistry letters》2010,20(14):4196-4200
A series of alkyne-containing type II inhibitors with potent inhibitory activity of T315I Bcr-Abl has been identified. The most active compound 4 exhibits an EC50 of less than 1 nM against wild-type Bcr-Abl and an EC50 of 10 nM against T315I mutant but is broadly active against a number of other kinases. 相似文献
11.
David McGowan Origène Nyanguile Maxwell D. Cummings Sandrine Vendeville Koen Vandyck Walter Van den Broeck Carlo W. Boutton Hendrik De Bondt Ludo Quirynen Katie Amssoms Jean-François Bonfanti Stefaan Last Klara Rombauts Abdellah Tahri Lili Hu Frédéric Delouvroy Katrien Vermeiren Geneviève Vandercruyssen Liesbet Van der Helm Erna Cleiren Pierre Raboisson 《Bioorganic & medicinal chemistry letters》2009,19(9):2492-2496
Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC50 = 400 nM and 270 nM, respectively) and selective (CC50 > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts. 相似文献
12.
Ronald C. Bernotas Schuyler Antane Rajesh Shenoy Van-Duc Le Ping Chen Boyd L. Harrison Albert J. Robichaud Guo Ming Zhang Deborah Smith Lee E. Schechter 《Bioorganic & medicinal chemistry letters》2010,20(5):1657-1660
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT6 receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT6 binding affinity with Ki values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC50 = 60 nM, Emax = 70%) and antagonists (6y: IC50 = 17 nM, Imax = 86%) were identified in a 5-HT6 adenylyl cyclase assay. 相似文献
13.
Frank Ruebsam Chinh V. Tran Lian-Sheng Li Sun Hee Kim Alan X. Xiang Yuefen Zhou Julie K. Blazel Zhongxiang Sun Peter S. Dragovich Jingjing Zhao Helen M. McGuire Douglas E. Murphy Martin T. Tran Nebojsa Stankovic David A. Ellis Alberto Gobbi Richard E. Showalter Stephen E. Webber Amit M. Shah Mei Tsan Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(2):451-458
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) < 10 nM; IC50 (1a) < 25 nM, EC50 (1b) = 16 nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F = 24%). 相似文献
14.
Andżelika Najda-Bernatowicz Mariusz Krawczyk Anna Stankiewicz-Drogoń Maria Bretner Anna M. Boguszewska-Chachulska 《Bioorganic & medicinal chemistry》2010,18(14):5129-5136
We synthesized new tropolone derivatives substituted with cyclic amines: piperidine, piperazine or pyrrolidine. The most active anti-helicase compound (IC50 = 3.4 μM), 3,5,7-tri[(4′-methylpiperazin-1′-yl)methyl]tropolone (2), inhibited RNA replication by 50% at 46.9 μM (EC50) and exhibited the lowest cytotoxicity (CC50) >1 mM resulting in a selectivity index (SI = CC50/EC50) >21. The most efficient replication inhibitor, 3,5,7-tri[(4′-methylpiperidin-1′-yl)methyl]tropolone (6), inhibited RNA replication with an EC50 of 32.0 μM and a SI value of 17.4, whereas 3,5,7-tri[(3′-methylpiperidin-1′-yl)methyl]tropolone (7) exhibited a slightly lower activity with an EC50 of 35.6 μM and a SI of 9.8. 相似文献
15.
《Bioorganic & medicinal chemistry》2016,24(8):1729-1740
A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin. 相似文献
16.
Pierre L. Beaulieu Eric Jolicoeur James Gillard Christian Brochu René Coulombe Nathalie Dansereau Jianmin Duan Michel Garneau Araz Jakalian Peter Kühn Lisette Lagacé Steven LaPlante Ginette McKercher Stéphane Perrault Martin Poirier Marc-André Poupart Timothy Stammers Louise Thauvette Bounkham Thavonekham George Kukolj 《Bioorganic & medicinal chemistry letters》2010,20(3):857-861
SAR studies at the N1-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC50 <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class. 相似文献
17.
Bhargav A. Patel Ramalingam Krishnan Nikhil Khadtare K.R. Gurukumar Amartya Basu Payal Arora Aaditya Bhatt Maulik R. Patel Dibyendu Dana Sanjai Kumar Neerja Kaushik-Basu Tanaji T. Talele 《Bioorganic & medicinal chemistry》2013,21(11):3262-3271
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(5):1407-1409
Hepatitis C virus (HCV) infection is one of the major health problems worldwide. If left untreated, it leads to liver cirrhosis, liver cancer and death. Herein, we report synthesis and anti-HCV activity of a new class of pyrimidine nucleosides possessing a 4′-carboxymethyl (9–16, 21 and 23) or 4′-carboxamide function (17–19 and 24). Among these, 10–12 (EC50 = 33.1–42.4 μM), 14 and 21 (EC50 = 43.4–59.5 μM) exhibited potent activity in HCV-1a replicon cells without any toxicity to parent Huh-7 cells (CC50 = >829–1055 μM). The anti-HCV activities demonstrated by this unusual class of compounds were superior to that of ribavirin (EC50 = 81.9 μM). Further, the most active analog, 12, was found to interact synergistically with ribavirin to inhibit HCV RNA replication. 相似文献
19.
Peng Zhan Xinyong Liu Zhenyu Li Zengjun Fang Zhong Li Defeng Wang Christophe Pannecouque Erik De Clercq 《Bioorganic & medicinal chemistry》2009,17(16):5920-5927
A novel synthetic route and anti-HIV activity evaluation of a new series of 2-(4-(2,4-dibromophenyl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives are described. Bioactivity assay indicated that most of the title compounds showed good activities against HIV-1. In particular, compound 7c displayed the most potent anti-HIV-1 activity (EC50 = 36.4 nM), inhibiting HIV-1 replication in MT-4 cells more effectively than NVP (by sevenfold) and DLV (by eightfold). The preliminary structure–activity relationships (SAR) of the newly synthesized congeners are discussed, and molecular modeling of compound 7c in complex with HIV-1 RT is described, allowing rationalization of some SAR conclusions. 相似文献
20.
Amogh Boloor Denise Hanway Maria Joshi David T. Winn Gabriel Mendez Marlena Walls Ping Wei Fuxin Qian Xiaoli Zhang Yuliang Zhang Michael E. Hepperle Xinqiang Li David A. Campbell Juan M. Betancort 《Bioorganic & medicinal chemistry letters》2009,19(19):5708-5711
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay. 相似文献