2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase

Pez, D; Leal, I; Zuccotto, F; Boussard, C; Brun, R; Croft, SL; Yardley, V; Perez, LMR; Pacanowska, DG; Gilbert, IH; (2003) 2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Bioorganic & medicinal chemistry, 11 (22). pp. 4693-4711. ISSN 0968-0896 DOI: https://doi.org/10.1016/j.bmc.2003.08.012

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This paper describes the synthesis of 4'-substituted and 3,4'- disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

Item Type: Article
Keywords: ligand interactions, flexible docking, scoring function, algorithm, design, acid
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Leishmaniasis Group
Malaria Centre
Neglected Tropical Diseases Network
PubMed ID: 14556785
Web of Science ID: 186134200002
URI: http://researchonline.lshtm.ac.uk/id/eprint/15837


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