Synthesis and mode of action studies of novel {2‐(3‐R‐1H‐1,2,4‐triazol‐5‐yl)phenyl}amines to combat pathogenic fungi

Abstract

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, 1H and 13C 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.

Combined Application of Tacrolimus with Cyproconazole, Hymexazol and Novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines as Antifungals: In Vitro Growth Inhibition and In Silico Molecular Docking Analysis to Fungal Chitin Deacetylase

“…Tacrolimus (99%) was purchased from Huaian Ruanke Trade, Ltd. (Huaian, China). Triazole 1 (4-chloro-2-(3-cyclobutyl-1 H -1,2,4-triazol-5-yl)aniline) and triazole 2 (2-(3-adamantan-1-yl)-1 H -1,2,4-triazol-5-yl)-4-chloroaniline) were obtained from Zaporizhzhia State Medical University, Ukraine [ 14 ]. Strains were cultivated on PDA for 6 days at 25 °C.…”

“…Control plates containing only PDA and deionized water were prepared in the same way. Inhibitory effects (I %) were determined by analyzing growth zone diameters and calculated as I % = [(C − T)/(C − 2.5 mm)]) × 100, where C (mm) represents the growth zone of control PDA + 1% DMSO and T (mm) represents the average growth zone in the presence of reference or test substances [ 14 ]. The enhancement or decline of microorganism growth was deducted from the activity of mixtures toward individual inhibition by substances.…”

“…In recent in vitro studies, we analyzed the antifungal activity of novel triazoles [ 14 ] ( Figure 1 ) against a range of fungi of agricultural importance. For almost half a century, azoles have played a preeminent role in effectively managing plant pathogens for the production of major crops such as cereals ( Triticum aestivum, Hordeum vulgare ), oilseed rape ( Brassica napus ), sugar beet ( Beta vulgaris ), bananas ( Musa spp.…”

“…Furthermore, azoles can also affect the biotransformation and bioaccumulation of other chemicals simultaneously administered with them by inhibiting CYP-catalyzed reactions [ 18 ]. Recently, we showed in an in vitro test the fungicidal activity of ten novel {2-(3-R)-1 H -1,2,4-triazol-5-yl]phenyl}amines along with the reference fungicides hymexazol and cyproconazole, which also have azole heterocyclic structures, against 12 fungal strains and oomycetes at a concentration of 50 mg/L; additionally, their nonmutagenicity was demonstrated with the reverse Salmonella mutagenicity assay (Ames test) [ 14 ].…”

NEW ROUTE FOR THE SYNTHESES OF SOME NOVEL DERIVATIVES OF 3-ARYL BENZO[d] THIAZOLE-2(3H)-IMINE FROM HIGH SUBSTITUTED THIOUREAS

“…Thioureas are used as the building blocks in the preparation of the heterocyclic compounds. Therefore, the syntheses of its derivatives have been the subject of gained interest as a precursor of the wide variety of biologically active compounds for many years [30][31][32]. Herein, we have prepared N-acyl-N'-aryl thiourea derivatives by the reaction of acyl halides, ammonium thiocyanate, and aryl amines with satisfactory yields.…”