title: Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds.
abstract: Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme (NNRTI) of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the NNRTI binding pocket, the R stereoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding S stereoisomers, as reflected by their 10(4)-fold lower K1 values. The R stereoisomers of several PETT derivatives inhibited recombinant RT in vitro with lower IC(50) values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All the R isomers once again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) at nanomolar concentrations whereas their enantiomers were substantially less potent. The lead compounds in the respective groups were further tested against the NNRTI-resistant HIV strains, A17 (Y181C mutant), and A17Var (Y181C+K103N mutant) and RT MDR (V106N). The results showed that the lead compounds were several logs more potent than the standard NNRTI nevirapine. Structure-activity relationship studies also revealed a preference for the pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of regiochemistry. Our data provides experimental evidence that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity.
authors.affiliation: Department of Chemistry, Parker Hughes Institute, 2699 Patton Road, Roseville, MN 55113, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: C
authors.initials: C
authors.lastname: Mao
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013890:Thiourea