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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 10(4)-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.

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