Arylated analogues of cypronazole: fungicidal effect and activity on human fibroblasts. Docking analysis and molecular dynamics simulations

HERRERA CANO, NATIVIDAD*; ANDUJAR, SEBASTIAN A.; THEODULOZ, CRISTINA; WUNDERLIN, DANIEL A.; SANTIAGO, ANA N.; SCHMEDA-HIRSCHMANN, GUILLERMO; ENRIZ, RICARDO D.; FERESIN, GABRIELA E.

Natural Products and Bioprospecting

Springer

Año: 2022 vol. 12

2192-2195

Triadimefon (TDM) and cyproconazole (CPZ) are two triazoles widely used as fungicides. Several azoles were synthesisedstarting from commercial TDM and CPZ. The compounds were evaluated against phytopathogenic filamentousfungi, including Aspergillus fumigatus (AF), A. niger (AN), A. ustus (AU), A. japonicus (AJ), A. terreus (AT), Fusarium oxysporumand Botrytis cinerea isolated from grapevine in the province of San Juan, Argentina. Three of the synthesisedcompounds (1-(Biphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one, 1; 2-(Biphenyl-4-yl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 3; 3-Cyclopropyl-2-(4?-fluorobiphenyl-4-yl)-1-(1H-1,2,4-triazol1-yl)butan-2-ol, 4)presented remarkable in vitro fungicidal properties, with better effects than TDM and CPZ on some of the target fungi.Cytotoxicity was assessed using human lung fibroblasts MRC5. Derivative 1, with IC50values of 389.4 μM, was lesstoxic towards MRC-5 human lung fibroblasts than commercial TDM (248.5 μM) and CPZ (267.4 μM). Docking analysisand molecular dynamics simulations suggest that the compounds present the same interaction in the bindingpocket of the CYP51B enzyme and with the same amino acids as CPZ. The derivatives investigated could be consideredbroad-spectrum but with some selectivity towards imperfect fungi.