Dihydrofolate reductase inhibitors: developments in antiparasitic chemotherapy

Background: Infections caused by parasitic protozoa present a growing health concern, particularly in developing parts of the world. Although malaria is clearly the most well-known and deadly of these diseases, infections caused by other parasites, such as Toxoplasma, Cryptosporidia and Trypanasoma are emerging infectious threats. The success of inhibitors of the enzyme dihydrofolate reductase (DHFR) against malaria has encouraged further exploration of this strategy against other parasites. Objective: This review presents antifolate inhibitors that have appeared in the patent literature and elaborates on their potency and selectivity against the DHFR enzyme from parasitic protozoa. Methods: The patent literature since 1994 was surveyed for antiparasitic DHFR inhibitors. Results/conclusions: Over the past several years, there have been a variety of novel, potent and selective inhibitors disclosed in patents, primarily from academic researchers. This review summarizes the recent development of antifolates as specific agents against parasitic protozoa.