SYNTHESIS AND ANTIVIRAL ACTIVITY OF BENZYL-SUBSTITUTED IMIDAZO[1,5-A]-1,3,5-TRIAZINE (5,8-DIAZA-7,9-DIDEAZAPURINE) DERIVATIVES

A variety of imidazo[1,5-alpha]-1,3, 5-triazine derivatives carrying C -, O-, and S-benzyl and/or 4-methylbenzyl groups were synthesized and examined for their inhibitory effects on the replication of ortho- and paramyxoviruses. The key compounds dihydroimidazo[1,5-alpha]-1,3,5-tr iazin-4(1H)-ones 3a,b,d were synthesized by chlorotrimethylsilane/HMDS -effected cyclization-rearrangement of the corresponding 5-(formylamin o)-5-R-2-mercaptopyrimidin-4(5H)-ones 2a,b,d (R = benzyl, 4-methylbenz yl, and 5-(benzyloxy)pentyl). Compounds 3a,b were further transformed into 4-thiones 5a,b and 4-dimethylamino derivatives 7a,b. Preparation of S-methyl, S-benzyl, and S-(4-methylbenzyl) derivatives 12-19 was ca rried out by the treatment of thioxo compounds 3b,d, 5b, and 8b in an alcohol/potassium carbonate system with methyl iodide or the appropria te aralkyl bromide. Simultaneous presence of the benzyl and thio struc tural units was found to be indispensable for any selective biological activity. Some 2-thio substituted compounds were specifically inhibit ory to some viruses, e.g., benzyl)thio]imidazo[1,5-alpha]-1,3,5-treiai n-4-one (13) and benzyl)thio]imidazo[1,5-alpha]-1,3,5-triazin-4-one (1 5) inhibited influenza A virus at a concentration of 4.1 and 5.3 mu M, and 6,8-dimethylimidazo[1,5-alpha]-1,3,5-triazin-4-one (16) and nzyl) thio]imidazo[1,5,-alpha]-1,3,5-triaziin-4-one (17) inhibited respirato ry syncyntial virus at a concentration of 21.9 and 15.7 mu M, respecti vely, that is, at concentrations that were 20-50-fold lower than the c ytotoxic concentrations. Compound 13 was inhibitory to respiratory syn cytial virus at a concentration of 1.4 mu M, that is, at a concentrati on that was 180-fold lower than the cytotoxic concentration to MDCK or Vero cells but only 7-fold lower than the cytotoxic concentration to HeLa cells. The 4-thiones 5a,b were nonselectively inhibitory to ortho - and paramyxoviruses at concentrations that coincided with their cyto toxic concentrations.