Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase

Abstract

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two α-methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized as nonnucleoside inhibitors (NNI) of human immunodeficiency virus (HIV) reverse transcriptase (RT). The R stereoisomers of all five compounds inhibited the recombinant RT in vitro with 100-fold lower IC 50 values. HI-509 R, HI-510 R, HI-511 R, HI-512 R and HI-513 R were active anti-HIV agents and inhibited HIV-1 replication in human peripheral blood mononuclear cells at nanomolar concentrations, whereas their enantiomers were inactive. Each of these five compounds was also active against NNI-resistant HIV-1 strains, with HI-511 R being the most active agent. When tested against the NNI-resistant HIV-1 strain A17 with a Y181C mutation in RT, HI-511 R was found to be 10,000-times more active than nevirapine, 5000-times more active than delavirdine, and 50-times more active than trovirdine. HI-511 R inhibited the HIV-strain A17 variant, containing RT mutations Y181C plus K103N, with an IC 50 value of 2.7 μM, whereas the IC 50 values of nevirapine, delavirdine, and trovirdine against this highly NNI-resistant HIV-1 strain were >100 μM.