Lipophilic antifolate trimetrexate is a potent inhibitor of trypanosoma cruzi: Prospect for chemotherapy of chagas' disease

Olga Senkovich, Vandanajay Bhatia, Nisha Garg, Debasish Chattopadhyay

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 PDA-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.

Original languageEnglish (US)
Pages (from-to)3234-3238
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume49
Issue number8
DOIs
StatePublished - Aug 2005

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Trimetrexate
Folic Acid Antagonists
Chagas Disease
Trypanosoma cruzi
Drug Therapy
Tetrahydrofolate Dehydrogenase
Pharmaceutical Preparations
Parasites
Pneumocystis Infections
Latin America
Poisons
Lethal Dose 50
Therapeutics
Acquired Immunodeficiency Syndrome
Public Health
Infection

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Lipophilic antifolate trimetrexate is a potent inhibitor of trypanosoma cruzi : Prospect for chemotherapy of chagas' disease. / Senkovich, Olga; Bhatia, Vandanajay; Garg, Nisha; Chattopadhyay, Debasish.

In: Antimicrobial Agents and Chemotherapy, Vol. 49, No. 8, 08.2005, p. 3234-3238.

Research output: Contribution to journalArticle

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