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.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

14-alpha Demethylase Inhibitors*/pharmacology ; 14-alpha Demethylase Inhibitors*/chemical synthesis ; 14-alpha Demethylase Inhibitors*/chemistry ; Drug Design* ; Molecular Dynamics Simulation* ; Antifungal Agents*/pharmacology ; Antifungal Agents*/chemical synthesis ; Antifungal Agents*/chemistry ; Pyridines*/pharmacology ; Pyridines*/chemical synthesis ; Pyridines*/chemistry ; Sterol 14-Demethylase*/metabolism ; Sterol 14-Demethylase*/chemistry; Structure-Activity Relationship ; Microbial Sensitivity Tests ; Fusarium/drug effects ; Penicillium ; Ascomycota/drug effects ; Colletotrichum/drug effects ; Botrytis/drug effects ; Molecular Structure ; Molecular Docking Simulation

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4 H -pyrano[3,2- c ]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against Sclerotinia sclerotiorum , Colletotrichum lagenarium , Botrytis cinerea , Penicillium digitatum , and Fusarium oxysporum at 16 μg/mL. The half maximal effective concentration (EC 50 ) values of compounds 7a , 7b , and 7f against B. cinerea were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC 50 = 0.670 μg/mL). Meanwhile, their half maximal inhibitory concentration (IC 50 ) 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 50 = 0.802 μg/mL). The fluorescent quenching tests of proteins showed that 7a and 7b had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of 7a and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.

0 (14-alpha Demethylase Inhibitors)
0 (Antifungal Agents)
0 (Pyridines)
EC 1.14.14.154 (Sterol 14-Demethylase)

Botrytis cinerea; Sclerotinia sclerotiorum; Fusarium oxysporum

Date Created: 20240504 Date Completed: 20240523 Latest Revision: 20240523

20240523

10.1021/acs.jmedchem.4c00032

38703119