Open AccessNovel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants
Author(s) -
Mei Zhu,
Yue Dou,
Ling Ma,
Biao Dong,
Fan Zhang,
Guoning Zhang,
Juxian Wang,
Jinming Zhou,
Shan Cen,
Yucheng Wang
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00043
Subject(s) - morpholine , hiv 1 protease , protease , carbamate , human immunodeficiency virus (hiv) , ligand (biochemistry) , chemistry , enzyme , ic50 , stereochemistry , combinatorial chemistry , active site , in vitro , biochemistry , biology , virology , medicinal chemistry , receptor
Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme K i of 0.092 nM and 0.21 nM, as well as antiviral IC 50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94% and 91%, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.