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2. Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors

Author

Andrea Cavalli, Véronique Hannaert, Shreedhara Gupta, Federica Gibellini, Paola Corona, Paul A.M. Michels, Antonio Carta, Stefania Ferrari, Puneet Saxena, Paola M. Costi, Erika Nerini, Giuseppe Paglietti, Davide Guerrieri, Mario Loriga, Rosaria Luciani, 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 P.A., Ferrari S., and Costi P.M.

Subjects
Stereochemistry, pteridine reductase inhibitors, antleishmania agents, pteridine derivatives, drug discovery, moelcular modelling, parasitology, Leishmania mexicana, Cell Line, Structure-Activity Relationship, chemistry.chemical_compound, Folic Acid, Dihydrofolate reductase, medicine, Humans, Structure–activity relationship, MOLECULAR MODELING, PARASITIC DISEASES, Nucleotide salvage, Leishmania major, Leishmania, chemistry.chemical_classification, biology, Chemistry, Drug discovery, Drug Synergism, Fibroblasts, Trypanocidal Agents, Pteridine reductase, Molecular Docking Simulation, DRUG DISCOVERY, Oxidative Stress, Pyrimethamine, Enzyme, Biochemistry, biology.protein, Molecular Medicine, Piperidine, Oxidoreductases, Hydrophobic and Hydrophilic Interactions, Protein Binding, medicine.drug
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.

Published
2012

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