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

doi:10.1007/s13659-022-00329-0

Natural Products and Bioprospecting ›› 2022, Vol. 12 ›› Issue (2): 9-9.DOI: 10.1007/s13659-022-00329-0

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

Natividad Herrera Cano^1,4, Sebastian A. Andujar², Cristina Theoduloz³, Daniel A. Wunderlin⁴, Ana N. Santiago⁵, Guillermo Schmeda-Hirschmann⁶, Ricardo D. Enriz², Gabriela E. Feresin¹

1 Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, CONICET–CCT San Juan, Av. Libertador General San Martín1109 (O), 5400 San Juan, Argentina;
2 Facultad de Química, Bioquímica y Farma- cia- IMIBIO-SL (CONICET), Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina;
3 Laboratorio de Cultivo Celular, Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, 3460000 Talca, Chile;
4 ICYTAC, CONICET and Universidad Nacional de Córdoba, Facultad de Ciencias Quími- cas, Departamento, Química Orgánica, Ciudad Universitaria, Bv. Juan Filloy s/n, 5000 Córdoba, Argentina;
5 INFIQC, CONICET and Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento Química Orgánica, Ciudad Universitaria, Haya de La Torre S/N, 5000 Córdoba, Argentina;
6 Labo- ratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, 3460000 Talca, Chile

Received:2021-12-03 Online:2022-04-26
Contact: Natividad Herrera Cano, E-mail:nherrerac@unc.edu.ar
Supported by:
This work was supported by the Consejo Nacional de Investigaciones Cientí- fcas y Técnicas (CONICET), Secretaría de Ciencia y Tecnología (SECYT-UNC), CICITCA UNSJ, IMIBIO-UNSL and Agencia Nacional de Promoción Científca y Tecnológica (ANPCyT). NHC gratefully acknowledges receipt of a fellowship from CONICET. G.S-H. and C.T. thank PIEI-QUIM-BIO, Universidad de Talca, for fnancial support.

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

Natividad Herrera Cano^1,4, Sebastian A. Andujar², Cristina Theoduloz³, Daniel A. Wunderlin⁴, Ana N. Santiago⁵, Guillermo Schmeda-Hirschmann⁶, Ricardo D. Enriz², Gabriela E. Feresin¹

1 Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, CONICET–CCT San Juan, Av. Libertador General San Martín1109 (O), 5400 San Juan, Argentina;
2 Facultad de Química, Bioquímica y Farma- cia- IMIBIO-SL (CONICET), Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina;
3 Laboratorio de Cultivo Celular, Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, 3460000 Talca, Chile;
4 ICYTAC, CONICET and Universidad Nacional de Córdoba, Facultad de Ciencias Quími- cas, Departamento, Química Orgánica, Ciudad Universitaria, Bv. Juan Filloy s/n, 5000 Córdoba, Argentina;
5 INFIQC, CONICET and Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento Química Orgánica, Ciudad Universitaria, Haya de La Torre S/N, 5000 Córdoba, Argentina;
6 Labo- ratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, 3460000 Talca, Chile

通讯作者: Natividad Herrera Cano, E-mail:nherrerac@unc.edu.ar
基金资助:
This work was supported by the Consejo Nacional de Investigaciones Cientí- fcas y Técnicas (CONICET), Secretaría de Ciencia y Tecnología (SECYT-UNC), CICITCA UNSJ, IMIBIO-UNSL and Agencia Nacional de Promoción Científca y Tecnológica (ANPCyT). NHC gratefully acknowledges receipt of a fellowship from CONICET. G.S-H. and C.T. thank PIEI-QUIM-BIO, Universidad de Talca, for fnancial support.

Abstract

Abstract: Triadimefon (TDM) and cyproconazole (CPZ) are two triazoles widely used as fungicides. Several azoles were synthesised starting from commercial TDM and CPZ. The compounds were evaluated against phytopathogenic filamentous fungi, including Aspergillus fumigatus (AF), A. niger (AN), A. ustus (AU), A. japonicus (AJ), A. terreus (AT), Fusarium oxysporum and Botrytis cinerea isolated from grapevine in the province of San Juan, Argentina. Three of the synthesised compounds (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 IC₅₀ values of 389.4 μM, was less toxic towards MRC-5 human lung fibroblasts than commercial TDM (248.5 μM) and CPZ (267.4 μM). Docking analysis and molecular dynamics simulations suggest that the compounds present the same interaction in the binding pocket of the CYP51B enzyme and with the same amino acids as CPZ. The derivatives investigated could be considered broad-spectrum but with some selectivity towards imperfect fungi.

Key words: Azoles, Antifungal cytotoxicity, Conformational and electronic analysis

摘要： Triadimefon (TDM) and cyproconazole (CPZ) are two triazoles widely used as fungicides. Several azoles were synthesised starting from commercial TDM and CPZ. The compounds were evaluated against phytopathogenic filamentous fungi, including Aspergillus fumigatus (AF), A. niger (AN), A. ustus (AU), A. japonicus (AJ), A. terreus (AT), Fusarium oxysporum and Botrytis cinerea isolated from grapevine in the province of San Juan, Argentina. Three of the synthesised compounds (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 IC₅₀ values of 389.4 μM, was less toxic towards MRC-5 human lung fibroblasts than commercial TDM (248.5 μM) and CPZ (267.4 μM). Docking analysis and molecular dynamics simulations suggest that the compounds present the same interaction in the binding pocket of the CYP51B enzyme and with the same amino acids as CPZ. The derivatives investigated could be considered broad-spectrum but with some selectivity towards imperfect fungi.

关键词: Azoles, Antifungal cytotoxicity, Conformational and electronic analysis

Natividad Herrera Cano, Sebastian A. Andujar, Cristina Theoduloz, Daniel A. Wunderlin, Ana N. Santiago, Guillermo Schmeda-Hirschmann, Ricardo D. Enriz, Gabriela E. Feresin. Arylated analogues of cypronazole: fungicidal effect and activity on human fibroblasts. Docking analysis and molecular dynamics simulations[J]. Natural Products and Bioprospecting, 2022, 12(2): 9-9.

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

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

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