De novo design of non-coordinating indolones as potential inhibitors for lanosterol 14-α-demethylase (CYP51)
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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. © 2014 The Pharmaceutical Society of Japan.
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Antifungal agent; Azole; Candida spp.; Lanosterol 14-α-demethylase (CYP51) inhibitor; Tetrahydroindol-4-one 1 (2 chlorophenyl) 6,7 dihidro 2,6,6 trimetil 1h indol 4 (5h)one; 1 (2,4 dichlorophenyl) 2,6,6 trimethyl 6,7 dihydro 1h indol 4 (5h)one; 1 (2,4 difluorophenyl) 2,6,6 trimethyl 6,7 dihydro 1h indol 4 (5h)one; 1 (4 chlorophenyl) 2,6,6 trimethyl 6,7 dihydro 1h indol 4 (5h)one; 1 (4 fluorophenyl) 2,6,6 trimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (2 chlorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (2 fluorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (2,4 dichlorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (2,4 difluorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (4 chlorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 (4 fluorophenyl) 6,6 dimethyl 6,7 dihydro 1h indol 4 (5h)one; 2 [2 (2 chlorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2 [2 (2 fuorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2 [2 (2,4 chlorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2 [2 (2,4 difluorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2 [2 (4 chlorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2 [2 (4 fluorophenyl) 2 oxoethyl] 5,5 dimethylcyclohexane 1,3 dione; 2,6,6 trimethyl 1 phenyl 6,7 dihydro 1h indol 4 (5h)one; 2,6,6 trimethyl 6,7 dihydro 1h indol 4 (5h)one; 5,5 dimethyl 2 (2 oxo 2 phenylethyl)cyclohexane 1,3 dione; 5,5 dimethyl 2 (2 oxopropyl)cyclohexane 1,3 dione; 6,6 dimethyl 2 phenyl 6,7 dihydro 1h indol 4 (5h)one; amphotericin; antifungal agent; fluconazole; indole derivative; indolone derivative; itraconazole; sterol 14alpha demethylase inhibitor; unclassified drug; unindexed drug; antifungal activity; article; Aspergillus fumigatus; Candida parapsilosis; Candida tropicalis; controlled study; drug design; drug structure; enzyme inhibition; in vitro study; minimum inhibitory concentration; molecular docking; molecular model; nonhuman; Pichia guilliermondii; randomized controlled trial (topic); 14-alpha Demethylase Inhibitors; Antifungal Agents; Drug Design; Fluconazole; Fungi; Indoles; Ligands; Microbial Sensitivity Tests; Sterol 14-Demethylase
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