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

• Published in: ChemMedChem 2011-05, Vol.6 (5), p.816-825
• Main Authors: Guillon, Rémi, Pagniez, Fabrice, Giraud, Francis, Crépin, Damien, Picot, Carine, Le Borgne, Marc, Morio, Florent, Duflos, Muriel, Logé, Cédric, Le Pape, Patrice
• Format: Article
• Language: English
• Subjects: 14-alpha Demethylase Inhibitors - chemical synthesis; 14-alpha Demethylase Inhibitors - chemistry; 14-alpha Demethylase Inhibitors - pharmacology; antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspergillus fumigatus - drug effects; Binding Sites; Candida albicans; Candida albicans - drug effects; Catalytic Domain; Chemical Sciences; Computer Simulation; CYP51 inhibitors; Drug Design; Life Sciences; Medicinal Chemistry; Microbial Sensitivity Tests; Microbiology and Parasitology; Mycology; Pharmaceutical sciences; Propanols - chemical synthesis; Propanols - chemistry; Propanols - pharmacology; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; Structure-Activity Relationship; structure-activity relationships; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; triazoles; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000530

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. Advancing antifungal compounds: New azole compounds are described with broad‐spectrum antifungal activities against Candida spp. and an Aspergillus fumigatus strain. Concerning fluconazole resistance, compound 17 shows a capacity to overcome CDR and ERG11 upregulation and to maintain antifungal activity despite a recognized critical CYP51 substitution in C. albicans isolates.