Design, Synthesis, and Biological Evaluation of 2,4-Diamino-5-methyl-6-substituted-pyrrolo2,3-dpyrimidines as Dihydrofolate Reductase Inhibitors

摘要

2,4-Diamino-5-methyl-6-(substituted-phenyl)thiopyrrolo2,3-dpyrimidines 4-11 were synthesized as dihydrofolate reductase (DHFR) inhibitors against opportunistic pathogens that afflict patients with AIDS. Synthesis was achieved from 2,4-diamino-5-methypyrrolo2,3-dpyrimidine and substituted phenylthiols under modified conditions reported by Gangjee et al. Some of these compounds were potent and selective against DHFR from both Toxoplasma gondii and Mycobacterium avium compared to mammalian DHFR. Compound 11 with a 1-naphthyl substituent is 16-fold more potent and equally selective against Toxoplasma gondii DHFR as the clinically used trimethoprim.