Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Bollini, Mariela¹  Gallardo-Macias, Ricardo¹  Spasov, Krasimir A.²  Tirado-Rives, Julian¹  Anderson, Karen S.²  Jorgensen, William L.¹ 

[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

关键词: Anti-HIV agents;    Computer-aided drug design;    NNRTIs;    Free-energy calculations;   

DOI  :  10.1016/j.bmcl.2012.11.115

来源: Elsevier

【 摘 要 】

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs le and if with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant. (C) 2012 Elsevier.Ltd. All rights reserved.

【 授权许可】

Free