共查询到20条相似文献,搜索用时 31 毫秒
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Zhao Wang Zhao Yu Dongwei Kang Jian Zhang Ye Tian Dirk Daelemans Erik De Clercq Christophe Pannecouque Peng Zhan Xinyong Liu 《Bioorganic & medicinal chemistry》2019,27(3):447-456
A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8?nM. Among them, the two most potent compounds 8i (EC50?=?59.5?nM) and 8k (EC50?=?54.8?nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50?=?12.8?μM) and comparable to doravirine (EC50?=?13?nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N?+?Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail. 相似文献
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Zhao-Sen Zeng Qiu-Qin He Yong-Hong Liang Xiao-Qing Feng Fen-Er Chen Erik De Clercq Jan Balzarini Christophe Pannecouque 《Bioorganic & medicinal chemistry》2010,18(14):5039-5047
Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a–z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N + Y181C RT HIV-1 strains than efavirenz. 相似文献
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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
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Bart Kesteleyn Katie Amssoms Wim Schepens Geerwin Hache Wim Verschueren Wim Van De Vreken Klara Rombauts Greet Meurs Patrick Sterkens Bart Stoops Lieven Baert Nigel Austin Jörg Wegner Chantal Masungi Inge Dierynck Stina Lundgren Daniel Jönsson Kevin Parkes Jan Willem Thuring 《Bioorganic & medicinal chemistry letters》2013,23(1):310-317
The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1–22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe–Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R3) at the para-position of the P1′ benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R1) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16–22) with EC50s on wild-type HIV-1 in the range of 0.8–1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS. 相似文献
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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
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Dai-Shi Su John J. Lim Elizabeth Tinney Bang-Lin Wan Mary Beth Young Kenneth D. Anderson Deanne Rudd Vandna Munshi Carolyn Bahnck Peter J. Felock Meiqing Lu Ming-Tain Lai Sinoeun Touch Gregory Moyer Daniel J. DiStefano Jessica A. Flynn Yuexia Liang Rosa Sanchez Sridhar Prasad Youwei Yan Neville J. Anthony 《Bioorganic & medicinal chemistry letters》2009,19(17):5119-5123