Synthesis and mode of action studies of novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines to combat pathogenic fungi
| Autor: | Lyudmyla M. Antypenko, Leif-Alexander Garbe, Karl G. Steffens, Fatuma Meyer, Sergiy Kovalenko, Kostiantyn Shabelnyk, Vera Meyer, Zhanar Sadykova |
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| Rok vydání: | 2019 |
| Předmět: |
Fusarium
Salmonella typhimurium Antifungal Agents Pharmaceutical Science Microbial Sensitivity Tests Colletotrichum coccodes 01 natural sciences Alternaria alternata Microbiology Structure-Activity Relationship Drug Discovery Fusarium oxysporum Colletotrichum higginsianum Botrytis cinerea Penicillium digitatum biology Molecular Structure 010405 organic chemistry Chemistry Aspergillus niger food and beverages Triazoles biology.organism_classification 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Drug Design Mitosporic Fungi |
| Zdroj: | Archiv der Pharmazie. 352(10) |
| ISSN: | 1521-4184 |
| Popis: | Due to their high specificity and efficacy, triazoles have become versatile antifungals to treat fungal infections in human healthcare and to control phytopathogenic fungi in agriculture. However, azole resistance is an emerging problem affecting human health as well as food security. Here we describe the synthesis of 10 novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines. Their structure was ascertained by liquid chromatography-mass spectrometry, 1 H and 13 C NMR, and elemental analysis data. Applying an in vitro growth assay, these triazoles show moderate to significant antifungal activity against the opportunistic pathogen Aspergillus niger, 12 fungi (Fusarium oxysporum, Fusarium fujikuroi, Colletotrichum higginsianum, Gaeumannomyces graminis, Colletotrichum coccodes, Claviceps purpurea, Alternaria alternata, Mucor indicus, Fusarium graminearum, Verticillium lecanii, Botrytis cinerea, Penicillium digitatum) and three oomycetes (Phytophtora infestans GL-1, P. infestans 4/91; R+ and 4/91; R-) in the concentration range from 1 to 50 µg/ml (0.003-2.1 μM). Frontier molecular orbital energies were determined to predict their genotoxic potential. Molecular docking calculations taking into account six common fungal enzymes point to 14α-demethylase (CYP51) and N-myristoyltransferase as the most probable fungal targets. With respect to effectiveness, structure-activity calculations revealed the strong enhancing impact of adamantyl residues. The shown nonmutagenicity in the Salmonella reverse-mutagenicity assay and no violations of drug-likeness parameters suggest the good bioavailability and attractive ecotoxicological profile of the studied triazoles. |
| Databáze: | OpenAIRE |
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