Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

• Published in: Bioorganic & medicinal chemistry 2010-06, Vol.18 (11), p.4056-4066
• Main Authors: Schormann, Norbert, Velu, Sadanandan E., Murugesan, Srinivasan, Senkovich, Olga, Walker, Kiera, Chenna, Bala C., Shinkre, Bidhan, Desai, Amar, Chattopadhyay, Debasish
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifolate; Antiparasitic agents; Biological and medical sciences; Chagas disease; Chagas Disease - drug therapy; Computer Simulation; Crystal structure; Crystallization; Crystallography, X-Ray; DHFR; Drug development; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - chemistry; Humans; Kinetoplast; Medical sciences; Parasitic disease; Pharmacology. Drug treatments; Protein Binding; Protozoan; Quinazolines; Tetrahydrofolate Dehydrogenase - chemistry; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - enzymology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.020

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.