Structural Features and Anti-Human Immunodeficiency Virus (HIV) Activity of the Isomers of 1-(2′,6′-Difluorophenyl)-1H,3H-Thiazolo[3,4-a]Benzimidazole, a Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitor

Abstract

The structural features, including the absolute configuration, of the enantiomers of 1-(2′,6′-difluorophenyl)-1 H,3 H-thiazolo[3,4- a]benzimidazole (TBZ; NSC 625487), the lead compound of a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs), are described. Diffractometric analysis revealed that TBZ, like other NNRTIs, assumes a butterfly-like conformation in which the phenyl ring at C1 is in an orthogonal orientation relative to the thiazolobenzimidazole system, and the 2′,6′-fluorine atoms form two intramolecular hydrogen bonds with H1 and one of the methylene protons at C3, respectively. The stereochemistry in solution, as confirmed by lanthanide shift reagent-assisted ‘H NMR, paralleled the situation present in the solid state. The in vitro anti-HIV activity of the two enantiomers was also evaluated and the results obtained showed that the R-(+) is more active than the S-(−) isomer in inhibiting HIV-1 replication. Resistance and cross-resistance to other NNRTIs as well as inhibitory effects on HIV-1 reverse transcriptase activity are also reported.