DESIGN AND SYNTHESIS OF NOVEL INHIBITORS OF HIV-1 REVERSE-TRANSCRIPTASE

A variety of N1-substituted pyrimido[5,4-f]benzo[1,4]thiazepines, 5, d esigned as conformationally constrained analogs of 1-[(2-hydroxyethoxy )methyl]-6-(phenylthio)thymine HEPT (1), were synthesized and evaluate d for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The preparation of these compounds was car ried out based on a Mannich-type cyclization of 6-[(2-aminophenyl)thio ]uracils followed by alkylation at N1 by a one-pot Vorbruggen reaction . The pyrimidobenzothiazepines were developed to give molecules with I C50 values in the micromolar range, as exemplified by l)oxy]methyl]-py rimido[5,4-f]benzo[1,4]thiazepine, 25, (IC50 = 0.64 mu M), the most ac tive compound of this series. The structural and electronic features o f this novel class of HIV-1 RT inhibitors are presented and compared w ith those of HEPT (1), TIBO (2), and nevirapine (3).