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Classical and Nonclassical Antifolates as Potential Antitumor, Antipneumocystis and Antitoxoplasma Agents



Inhibition of folate metabolizing enzymes remains a viable goal in the treatment of cancer, of bacterial infections and of opportunistic infections in patients with immune compromized systems. The clinically useful antifolates methotrexate (MTX), trimetrexate (TMQ), trimethoprim (TMP), pyrimethamine and 2D1694 (tomudex) inhibit the enzymes dihydrofolate reductase (DHFR) or thymidylate synthase (TS). The recent antitumor results obtained with tomudex and the antipneumocystis results with
TMQ along with leucovorin rescue have provided significant stimulus to the synthesis and biological testing of antifolates. In addition, X-ray crystallography studies of the enzymes with computer assisted molecular modeling have allowed for significant studies in the development of novel antifolates. This review highlights recent advances in the computer assisted rational design, synthesis and biological evaluation of substituted classical and nonclassical bicyclic 6-6 and 6-5 ring fused antifolates, tricyclic 6-6-6 and 6-5-6 ring-fused antifolates and tetracyclic 6-6-6-6 ring-fused antifolates as anticancer, antipneumocystis and antitoxoplasma agents.
