349613-86-1Relevant academic research and scientific papers
Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors
Corona, Paola,Gibellini, Federica,Cavalli, Andrea,Saxena, Puneet,Carta, Antonio,Loriga, Mario,Luciani, Rosaria,Paglietti, Giuseppe,Guerrieri, Davide,Nerini, Erika,Gupta, Shreedhara,Hannaert, Véronique,Michels, Paul A. M.,Ferrari, Stefania,Costi, Paola M.
, p. 8318 - 8329 (2012)
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.
