Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

Rémi Guillon; Fabrice Pagniez; Francis Giraud; Damien Crépin; Carine Picot; Marc Le Borgne; Florent Morio; Muriel Duflos; Cédric Logé; Patrice Le Pape

doi:10.1002/cmdc.201000530

Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols

ChemMedChem. 2011 May 2;6(5):816-25. doi: 10.1002/cmdc.201000530. Epub 2011 Mar 2.

Authors

Rémi Guillon¹, Fabrice Pagniez, Francis Giraud, Damien Crépin, Carine Picot, Marc Le Borgne, Florent Morio, Muriel Duflos, Cédric Logé, Patrice Le Pape

Affiliation

¹ Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, Cibles et Médicaments des Infections, de l'Immunité et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, Nantes, France.

PMID: 21370476
DOI: 10.1002/cmdc.201000530

Abstract

As part of our studies focused on the design of 1-[((hetero)aryl- and piperidinylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, we report the development of new extended benzylamine derivatives substituted at the para position by sulfonamide or retrosulfonamide groups linked to alkyl or aryl chains. These molecules have broad-spectrum antifungal activities not only against Candida spp., including fluconazole-resistant strains, but also against a filamentous species (A. fumigatus). Concerning fluconazole resistance, selected compounds exhibit the capacity to overcome CDR and ERG11 gene upregulation and to maintain antifungal activity despite a recognized critical CYP51 substitution in C. albicans isolates. Synthesis, investigation of the mechanism of action by sterol analysis in a C. albicans strain, and structure-activity relationships (SARs) are reported.

MeSH terms

14-alpha Demethylase Inhibitors / chemical synthesis
14-alpha Demethylase Inhibitors / chemistry
14-alpha Demethylase Inhibitors / pharmacology
Antifungal Agents / chemical synthesis*
Antifungal Agents / chemistry
Antifungal Agents / pharmacology
Aspergillus fumigatus / drug effects
Binding Sites
Candida albicans / drug effects
Catalytic Domain
Computer Simulation
Drug Design
Microbial Sensitivity Tests
Propanols / chemical synthesis
Propanols / chemistry*
Propanols / pharmacology
Sterol 14-Demethylase / chemistry
Sterol 14-Demethylase / metabolism
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology
Triazoles / chemical synthesis*
Triazoles / chemistry*
Triazoles / pharmacology

Substances

14-alpha Demethylase Inhibitors
4-(((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)methylamino)methyl)-N-(phenyl)benzenesulfonamide
Antifungal Agents
Propanols
Sulfonamides
Triazoles
1,2,4-triazole
Sterol 14-Demethylase