Structure-Based Selectivity Optimization of Piperidine鈥揚teridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors
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- 作者：Paola Corona ; Federica Gibellini ; Andrea Cavalli ; Puneet Saxena ; Antonio Carta ; Mario Loriga ; Rosaria Luciani ; Giuseppe Paglietti ; Davide Guerrieri ; Erika Nerini ; Shreedhara Gupta ; V茅ronique Hannaert ; Paul A. M. Michels ; Stefania Ferrari ; Paola M. Costi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：October 11, 2012
- 年：2012
- 卷：55
- 期：19
- 页码：8318-8329
- 全文大小：642K
- 年卷期：v.55,no.19(October 11, 2012)
- ISSN：1520-4804
文摘
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鈥檚 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.