Stereochemistry as a Major Determinant of the Anti-HIV Activity of Chiral Naphthyl Thiourea Compounds

Abstract

Eleven chiral naphthyl thiourea (CNT) compounds were synthesized as non-nucleoside inhibitors (NNI) of the reverse transcriptase (RT) enzyme of HIV-1. Molecular modelling studies indicated that, because of the asymmetric geometry of the NNI binding pocket, the ‘R” stereoisomers would fit the NNI binding pocket of the HIV-1 RT much better than the corresponding ‘S” stereoisomers, as reflected by their 10⁴-fold lower Ki values. The ‘R” stereoisomers of all 11 compounds inhibited the recombinant RT in vitro with lower IC₅₀ values than their enantiomers. Of seven CNT compounds whose ‘R” stereoisomers exhibited nanomolar IC₅₀ values against recombinant RT, five were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All five ‘R” stereoisomers were active anti-HIV agents and inhibited the replication of the HIV-1 strains HTLV-IIIB (NNI-sensitive), A17 (NNI- resistant, Y181C mutant RT) and A17Var (NNI- resistant, Y181C plus K103N mutant RT), as well as primary HIV-1 isolates from AIDS patients in human PBMC at nanomolar concentrations, whereas their enantiomers were inactive. The lead compounds, 1R and 5R, were 3 log more potent than the standard NNI drug nevirapine against the NNI-resistant HIV-1 strains. Our data establish the stereochemistry as a major determinant of the potency of this new class of NNI.