NOVEL 1,1,3-TRIOXO-2H,4H-THIENO [3,4-E][1,2,4] THIADIAZINE DERIVATIVES AS NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS THAT INHIBIT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION

The ,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) represen t a recently discovered chemical class of non-nucleoside reverse trans criptase inhibitors that selectively block human immunodeficiency viru s type 1 replication. In a search for a better understanding of their mode of binding and with the aim of obtaining novel lead compounds, a second series of TTD derivatives was synthesized and evaluated for ant iviral activity. The design of the new compounds was based on a variet y of chemical modifications which were carried out in the original pro totype 20a (QM 96521). Substitution of a halogen at the meta position of the N-2 benzyl group resulted in an improvement of the antiviral ac tivity by 1 order of magnitude. Compounds bearing at the N-4 position a cyanomethyl, propargyl, or benzyl substituent were found to be the m ost potent of the series. Modifying the thieno[3,4-e] ring fused to th e 1,2,4-thiadiazine moiety to other heterocyclic ring systems decrease d the potency. The results obtained in this investigation have provide d new indications for the design of even more effective TTDs.