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

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Corona P, Gibellini F, Cavalli A, Saxena P, Carta A, Loriga M, Luciani R, Paglietti G, Guerrieri D, Nerini E, Gupta S, Hannaert V, Michels PA, Ferrari S, Costi PM

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. Epub 2012 Sep 19.

PubMed ID

22946585 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Dihydrofolate reductase	Ki (nM)	0	N/A	N/A	Details
Methotrexate	Thymidylate synthase	Ki (nM)	600	N/A	N/A	Details