title: Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: viral potency of chiral PETT derivatives.
abstract: Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the non-nucleoside inhibitors (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 K(i) values. The "R" stereoisomers of several PETT derivatives inhibited the 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 (PBMCs). All the "R" isomers again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strains HTLV(IIIB) in PBMCs at nanomolar concentrations whereas their enantiomers were less potent. The lead compounds for the respective groups were further tested against A17 (NNRTI-resistant, Y181C mutant RT), and A17Var (NNI-resistant Y181C +/- K103N mutant RT) as well as multidrug resistant viral strains. The results indicated that the lead compounds were several logs more potent than the standard NNRTI drug nevirapine. Structure-activity relationship among the derivatives showed preference of pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of both the stereochemistry as well as regiochemistry. Our data provides experimental evidence that the stereochemistry and the regiochemistry of non-nucleoside inhibitors can profoundly affect their anti-HIV activity.
authors.affiliation: Department of Chemistry, Structural Biology and Virology, Parker Hughes Institute, 2657 Patton Road, St. Paul, MN 55113, USA.
authors.forename: Taracad K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: Chen
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*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D013844:Thiazoles; D014230:Triazoles; C062942:2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole