Premium
Design, Biologic Evaluation, and SAR of Novel Pseudo‐peptide Incorporating Benzheterocycles as HIV‐1 Protease Inhibitors
Author(s) -
He Meizi,
Zhang Hang,
Yao Xiaojian,
Eckart Michael,
Zuo Elizabeth,
Yang Ming
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.00995.x
Subject(s) - substituent , hiv 1 protease , chemistry , stereochemistry , isostere , protease , sulfonamide , protease inhibitor (pharmacology) , potency , pyrrolidine , isopropyl , docking (animal) , hydrogen bond , enzyme , biochemistry , human immunodeficiency virus (hiv) , in vitro , organic chemistry , biology , medicine , nursing , molecule , antiretroviral therapy , viral load , immunology
A series of novel HIV‐1 protease inhibitors based on the (hydroxyethylamino)‐sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P 2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the ‐CH 2 ‐ of P 1 ‐P 2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P 1 ′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV‐1 protease with an IC 50 value of 5 n m , also exhibited good anti‐SIV activity (EC 50 = 0.8 μ m ) with low toxicity (TC 50 > 100 μ m ). The flexible docking of inhibitor 23 to HIV‐1 protease active site rationalized the interactions with protease.