title: De novo design of non-coordinating indolones as potential inhibitors for lanosterol 14-α-demethylase (CYP51).
abstract: The development of antifungal drugs that inhibit lanosterol 14-α-demethylase (CYP51) via non-covalent ligand interactions is a strategy that is gaining importance. A series of novel tetraindol-4-one derivatives with 1- and 2-(2,4-substituted phenyl) side chains were designed and synthesized based on the structure of CYP51 and fluconazole. The antifungal activities of these derivatives against eight human pathogenic filamentous fungi and yeast strains were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds 8a-g displayed activity against Candida tropicalis, Candida guilliermondii and Candida parapsilosis with a minimum inhibitory concentration (MIC) value until 8 µg mL(-1), on the other hand compounds 7a-g showed activity against Aspergillus fumigatus with a MIC value of 31.25 µg mL(-1). A molecular modeling study of the binding interactions between compounds 6, 7d, 8g and the active site of MtCYP51 was conducted based on the computational docking results.
authors.affiliation: Posgrado en Ciencias en Bioprocesos, Universidad Autónoma de San Luis Potosí
authors.forename: Rodolfo
authors.initials: R
authors.lastname: González-Chávez
authors.forename: Roberto
authors.initials: R
authors.lastname: Martínez
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Torre-Bouscoulet
authors.forename: Marco
authors.initials: M
authors.lastname: Gallo
authors.forename: Marco Martín
authors.initials: MM
authors.lastname: González-Chávez
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D015725:Fluconazole / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D058886:Sterol 14-Demethylase / Q000378:metabolism*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D007211:Indoles; D008024:Ligands; D015725:Fluconazole; D058886:Sterol 14-Demethylase