title: Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors.
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.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Muroni 23/a, 07100 Sassari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Corona
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Puneet
authors.initials: P
authors.lastname: Saxena
authors.forename: Antonio
authors.initials: A
authors.lastname: Carta
authors.forename: Mario
authors.initials: M
authors.lastname: Loriga
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paglietti
authors.forename: Davide
authors.initials: D
authors.lastname: Guerrieri
authors.forename: Erika
authors.initials: E
authors.lastname: Nerini
authors.forename: Shreedhara
authors.initials: S
authors.lastname: Gupta
authors.forename: Véronique
authors.initials: V
authors.lastname: Hannaert
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.forename: Paola M
authors.initials: PM
authors.lastname: Costi
mesh_terms: D002460:Cell Line; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology*; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology; D007894:Leishmania mexicana / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011739:Pyrimethamine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014344:Trypanocidal Agents; D005492:Folic Acid; D010088:Oxidoreductases; C085592:pteridine reductase; D011739:Pyrimethamine