2. Academic Validation
  3. Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors

Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors

  • J Med Chem. 2012 Oct 11;55(19):8318-29. doi: 10.1021/jm300563f.
Paola Corona 1,  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,  Paola M Costi
Affiliations

Affiliation

  • 1 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Muroni 23/a, 07100 Sassari, Italy.
PMID: 22946585 DOI: 10.1021/jm300563f
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.

Figures