Folate-based antimicrobial agents

Based on the significant differences in transport characteristics of folate coenzymes that exist among mammalian versus microbial cells, a series of nonglutamated inhibitors of dihydrofolate reductase (DHFR) and glycinamideribonucleotide formyltransferase (GARFT) were designed, synthesized and evaluated as potential antimicrobial agents. The nonglutamated DHFR inhibitors are analogues of the antitumor agent 10-deazaaminopterin (10-DAM) in which the benzoyl glutamate moiety is replaced with pyridyl (8a and 8b), quinolyl (8c and 8d) or naphthyl (8e) group, and they were evaluated for differential inhibition of rat liver, Pneumocystis carinii (P. carinii) and Toxoplasma gondii (T. gondii) DHFR. The water soluble 2-quinolyl substituted compound 8c was most active in this series. It exhibited greater potency and selectivity than pyrimethamine in inhibiting both P. carinii and T. gondii DHFR relative to the rat liver enzyme. Its selectivity indices (RL/Pc = 12, RL/Tx = 17) for both P. carinii ;The nonglutamated GARFT inhibitors are analogues of 10-formyl-5,8,10-trideazafolic acid (FTDF). The benzoyl-glutamate moiety of FTDF was replaced with different aromatic rings to synthesize the first series of compounds 18a-f. Reduction of the 10-formyl group of 18a-f to their respective 10-hydroxymethyl derivatives gave the second series of compounds 19a-f. The third series of compounds in this class, 14a-b and 15a-b, bear a 2-desamino-2-methyl substituent at the quinazoline ring. Five of these compounds bearing the 2-amino-10-deaza-10-formyl pharmacophore (18a, 18b, 18d, 18e and 18f) were shown to be powerful inhibitors of both L. casei and recombinant mouse GARFT. 2-Amino-6-(2...