title: Design, synthesis, and biological evaluation of 1-[(biarylmethyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as potent antifungal agents: new insights into structure-activity relationships.
abstract: We recently reported the design and synthesis of azole antifungal agents with a focus on modifications to the side chain appended to the propanol group. Herein we have identified a series of new 1-[(biarylmethyl)methylamino] derivatives with broad-spectrum antifungal activities against the most prevalent human pathogenic fungi (Candida spp. and Aspergillus fumigatus). Compounds containing a flexible benzylamine moiety were clearly shown to yield the best antifungal activities, without the need for a hydrogen-bond acceptor substituent directly attached to the para position. We were also able to determine that selected compounds are able to overcome gene overexpression and point mutations that lead to reduced susceptibility or resistance against current treatments, such as fluconazole. As the minor differences observed with small structural modifications cannot be explain with only a three-dimensional model of CYP51, adequate physicochemical parameters must be evaluated in terms of antifungal potency, bioavailability, and toxicity. Therefore, structure-activity relationship studies such as these reveal new insights for the development of future antifungal therapies.
authors: 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, 1 rue Gaston Veil, Nantes 44035 Cedex 1, France.
authors: Rémi
authors: R
authors: Guillon
authors: Fabrice
authors: F
authors: Pagniez
authors: Charlotte
authors: C
authors: Rambaud
authors: Carine
authors: C
authors: Picot
authors: Muriel
authors: M
authors: Duflos
authors: Cédric
authors: C
authors: Logé
authors: Patrice
authors: P
authors: Le Pape
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects*; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D015725:Fluconazole / Q000737:chemistry; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D020005:Propanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D020005:Propanols; D014230:Triazoles; C045575:1,2,4-triazole; D015725:Fluconazole; D058886:Sterol 14-Demethylase