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.

Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors / Paola, Corona; Gibellini, Federica; Saxena, Puneet; Luciani, Rosaria; Guerrieri, Davide; Nerini, Erika; Ferrari, Stefania; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 55 (19):(2012), pp. in stampa-in stampa. [10.1021/jm300563f]

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

GIBELLINI, Federica;SAXENA, PUNEET;LUCIANI, Rosaria;GUERRIERI, Davide;NERINI, Erika;FERRARI, Stefania;COSTI, Maria Paola
2012

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.
55 (19)
in stampa
in stampa
Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors / Paola, Corona; Gibellini, Federica; Saxena, Puneet; Luciani, Rosaria; Guerrieri, Davide; Nerini, Erika; Ferrari, Stefania; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 55 (19):(2012), pp. in stampa-in stampa. [10.1021/jm300563f]
Paola, Corona; Gibellini, Federica; Saxena, Puneet; Luciani, Rosaria; Guerrieri, Davide; Nerini, Erika; Ferrari, Stefania; Costi, Maria Paola
File in questo prodotto:
File Dimensione Formato  
jm300563f.pdf

non disponibili

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 4.59 MB
Formato Adobe PDF
4.59 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/816291
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 34
  • ???jsp.display-item.citation.isi??? 33
social impact