SYNTHESIS OF NONNUCLEOSIDE ANALOGS OF TOYOCAMYCIN, SANGIVAMYCIN, AND THIOSANGIVAMYCIN - THE EFFECT OF CERTAIN 4-SUBSTITUENT AND 4,6-SUBSTITUENT ON THE ANTIVIRAL ACTIVITY OF PYRROLO[2,3-D]PYRIMIDINES

A number of 4-substituted 7-(ethoxymethyl)- and 7-[(2-methoxyethoxy)me thyl]pyrrolo[2,3-d- pyrimidine-5-carbonitrile and -5-thiocarboxamide d erivatives and several 7-substituted ,6-diaminopyrrolo[2,3-d]pyrimidin e-5-carbonitrile, -5-carboxamide, and -5-thiocarboxamide analogs relat ed to the nucleoside antibiotics toyocamycin and sangivamycin were pre pared and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1). Biologically, modifications at t he 4-position were not well tolerated in cell culture, and in almost a ll cases no activity against HCMV or HSV-1 was observed. Furthermore, none of the compounds inhibited the growth of L1210 murine leukemic ce lls in vitro. In sharp contrast to the 4-substituted compounds, all of the 4,6-diamino 5-nitrile and the 5-thioamide analogs were active aga inst HCMV, whereas the 5-carboxamides were inactive. The corresponding 4-amino 6-methylamino and 6-dimethylamino 5-nitrile analogs were inac tive against HCMV, establishing that an amino group at both C-4 and C- 6 is a likely requirement for antiviral activity. Overall, our results demonstrate that an amino group at C-4 and a thioamide moiety at C-5 of a 7-substituted pyrrolo[2,3-d]pyrimidine are essential for activity against HCMV, whereas a 4,6-diamino analog does not necessarily requi re a thioamide group at C-5 for activity against HCMV.