title: Lipophilic antifolate trimetrexate is a potent inhibitor of Trypanosoma cruzi: prospect for chemotherapy of Chagas' disease.
abstract: Trypanosoma cruzi, a protozoan parasite, is the causative agent for Chagas' disease, which poses serious public health problem in Latin America. The two drugs available for the treatment of this disease are effective only against recent infections and are toxic. Dihydrofolate reductase (DHFR) has a proven track record as a drug target. The lipophilic antifolate trimetrexate (TMQ), which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients, is a potent inhibitor of T. cruzi DHFR activity, with an inhibitory constant of 6.6 nM. The compound is also highly effective in killing T. cruzi parasites. The 50 and 90% lethal dose values against the trypomastigote are 19 and 36 nM, and the corresponding values for the amastigote form are 26 and 72 nM, respectively. However, as TMQ is also a good inhibitor of human DHFR, further improvement of the selectivity of this drug would be preferable. Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas' disease.
authors.affiliation: University of Alabama at Birmingham, CBSE-250, 1025 18th Street South, Birmingham, AL 35294, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Senkovich
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.forename: Nisha
authors.initials: N
authors.lastname: Garg
authors.forename: Debasish
authors.initials: D
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D004338:Drug Combinations; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005965:Glucuronates / Q000494:pharmacology*; D006801:Humans; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016597:Trimetrexate / Q000031:analogs & derivatives* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004338:Drug Combinations; D005493:Folic Acid Antagonists; D005965:Glucuronates; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; C056321:trimetrexate glucuronate; D016597:Trimetrexate