STRUCTURAL FEATURES AND ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) ACTIVITY OF THE ISOMERS OF IFLUOROPHENYL)-1H,3H-THIAZOLO[3,4-A]BENZIMIDAZOLE, A POTENT NONNUCLEOSIDE HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR

The structural features, including the absolute configuration, of the enantiomers of difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ ; NSC 625487), the lead compound of a new class of human immunodeficie ncy virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibito rs (NNRTIs), are described. Diffractometric analysis revealed that TBZ , like other NNRTIs, assumes a butterfly-like conformation in which th e phenyl ring at C1 is in an orthogonal orientation relative to the th iazolobenzimidazole system, and the 2',6'-fluorine atoms form two intr amolecular hydrogen bonds with H1 and one of the methylene protons at C3, respectively. The stereochemistry in solution, as confirmed by lan thanide shift reagent-assisted H-1 NMR, paralleled the situation prese nt in the solid state. The in the vitro anti-HIV activity of the two e nantiomers was also evaluated and the results obtained showed that the R-(+) is more active than the S-(-) isomer in inhibiting HIV-1 replic ation. Resistance and cross-resistance to other NNRTIs as well as inhi bitory effects on HIV-1 reverse transcriptase activity are also report ed.