24-Diamino-5-methyl-6-substituted Arylthio-furo23-dpyrimidines as Novel Classical and Nonclassical Antifolates as Potential Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

摘要

A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}-l-glutamic acid >5 and 11 nonclassical antifolates >6–>16 were designed, synthesized, and evaluated as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds >6–>16 were synthesized from >20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid >21 followed by saponification gave the classical analog >5. Compound >5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog >5 was a nanomolar inhibitor and remarkably selective inhibitor of P. carinii DHFR and M. avium DHFR at 263-fold and 2107-fold respectively compared to mammalian DHFR. The nonclassical analogs >6–>16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.