Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 20, Pages 7938-7948Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00687
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Funding
- Ministry of Education and Research (MIUR) [2012-74BNKN]
- Ministry of Foreign Affairs (Progetto di Grande Rilevanza Italia-Albania) [PGR 00102]
- Wellcome Trust [082596, 094090]
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The bifunctional enzyme N-5,N-10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (Poll)) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 mu M, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 mu M). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP(+). and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors.
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