Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors
Journal of Medicinal Chemistry2012Vol. 55(19), pp. 8318–8329
Citations Over TimeTop 10% of 2012 papers
Paola Corona, Federica Gibellini, Andrea Cavalli, Puneet Saxena, Antonio Carta, Mario Loriga, Rosaria Luciani, Giuseppe Paglietti, Davide Guerrieri, Erika Nerini, Shreedhara Gupta, Véronique Hannaert, Paul A.M. Michels, Stefania Ferrari, Maria Paola Costi
Abstract
The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.
Related Papers
- → Folic Acid: Crystal Structure and Implications for Enzyme Binding(1980)45 cited
- → Dihydrofolate reductase and antifolate resistance in malaria(1998)38 cited
- → Stereochemistry of reduction of the vitamin folic acid by dihydrofolate reductase(1985)36 cited
- → Inhibition of Dihydrofolate Reductase and Cell Growth by Antifolates in a Methotrexate-Resistant Cell Line(1984)7 cited
- → Conformational analysis of folates and folate analogues(2009)7 cited