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

The structural features, including the absolute configu ration, of the enantiomers of 1-(2',6'-difluorophenyl): 1H,3H-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 1H NMR, parallelel 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.