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J Med Chem. 2012 Oct 11;55(19):8318-29. doi: 10.1021/jm300563f. Epub 2012 Sep 19.

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

Author information

1
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Muroni 23/a, 07100 Sassari, Italy.

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.

PMID:
22946585
DOI:
10.1021/jm300563f
[Indexed for MEDLINE]

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