Design, Synthesis, Bioactive Evaluation, and Molecular Dynamics Simulation of Novel 4 H -Pyrano[3,2- c ]pyridine Analogues as Potential Sterol 14α-Demethylase (CYP51) Inhibitors

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (10), p.7954-7972
• Main Authors: Bao, Ailing, Jiang, Wenjing, Xie, Xiansong, Wang, Deyuan, Deng, Ziquan, Wang, Jingwen, Li, Weiyi, Tang, Xiaorong, Yan, Yingkun
• Format: Article
• Language: English
• Subjects: 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; Ascomycota - drug effects; Botrytis - drug effects; Colletotrichum - drug effects; Drug Design; Fusarium - drug effects; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Penicillium; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00032

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4 -pyrano[3,2- ]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against , , , , and at 16 μg/mL. The half maximal effective concentration (EC ) values of compounds , , and against were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC = 0.670 μg/mL). Meanwhile, their half maximal inhibitory concentration (IC ) values against CYP51 were 0.377, 0.611, and 0.748 μg/mL, respectively, representing that they also possessed better inhibitory activities than epoxiconazole (IC = 0.802 μg/mL). The fluorescent quenching tests of proteins showed that and had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.