Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase.

Article Details

Citation

Copy to clipboard

Schormann N, Velu SE, Murugesan S, Senkovich O, Walker K, Chenna BC, Shinkre B, Desai A, Chattopadhyay D

Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase.

Bioorg Med Chem. 2010 Jun 1;18(11):4056-66. doi: 10.1016/j.bmc.2010.04.020. Epub 2010 Apr 9.

PubMed ID

20452776 [ View in PubMed

]

Abstract

Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Trimetrexate	Dihydrofolate reductase	IC 50 (nM)	80.9	N/A	N/A	Details