Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

Journal Article · Fri Sep 17 04:00:00 EDT 2010 · Bioorgan. Med. Chem.

DOI:https://doi.org/10.1016/j.bmc.2010.04.020· OSTI ID:1002640

Schormann, Norbert; Velu, Sadanandan E; Murugesan, Srinivasan; Senkovich, Olga; Walker, Kiera; Chenna, Bala C; Shinkre, Bidhan; Desai, Amar; Chattopadhyay, Debasish ^[1]

---

1. UAB

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002640
• Journal Information: Bioorgan. Med. Chem., Journal Name: Bioorgan. Med. Chem. Journal Issue: (11) ; 06, 2010 Vol. 18
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
BINDING ENERGY
CRYSTAL STRUCTURE
ENZYMES
OXIDOREDUCTASES
PARASITES
SYNTHESIS
TARGETS
TRYPANOSOMA