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Synthesis and mode of action studies of novel {2‐(3‐R‐1 H ‐1,2,4‐triazol‐5‐yl)phenyl}amines to combat pathogenic fungi
Author(s) -
Antypenko Lyudmyla,
Sadykova Zhanar,
Shabelnyk Kostiantyn,
Meyer Fatuma,
Kovalenko Sergiy,
Meyer Vera,
Garbe LeifAlexander,
Steffens Karl
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900092
Subject(s) - botrytis cinerea , fusarium oxysporum , alternaria alternata , biology , fusarium , aspergillus fumigatus , pathogenic fungus , spore germination , microbiology and biotechnology , fungus , botany , spore
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‐1 H ‐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.