Design, Synthesis and Fungicidal Activity of New 1,2,4-Triazole Derivatives Containing Oxime Ether and Phenoxyl Pyridinyl Moiety

Abstract

A series of novel 1,2,4-triazole derivatives containing oxime ether and phenoxy pyridine moiety were designed and synthesized. The new compounds were identified by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). Compound (Z)-1-(6-(4-nitrophenoxy)pyridin-3-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-methyl oxime (5a18) was further confirmed by X-ray single crystal diffraction. Their antifungal activities were evaluated against eight phytopathogens. The in vitro bioassays indicated that most of the title compounds displayed moderate to high fungicidal activities. Compound (Z)-1-(6-(4-bromo-2-chlorophenoxy)pyridin-3-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-methyl oxime (5a4) exhibited a broad-spectrum antifungal activities with the EC₅₀ values of 1.59, 0.46, 0.27 and 11.39 mg/L against S. sclerotiorum, P. infestans, R. solani and B. cinerea, respectively. Compound (Z)-1-(6-(2-chlorophenoxy)pyridin-3-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime (5b2) provided the lowest EC₅₀ value of 0.12 mg/L against S. sclerotiorum, which were comparable to the commercialized difenoconazole. Moreover, homologous modeling and molecular docking disclosed possible binding modes of compounds 5a4 and 5b2 with CYP51. This work provided useful guidance for the discovery of new 1,2,4-triazole fungicides.

Keywords: 1,2,4-triazole; CYP51; fungicidal activity; oxime ether; phenoxy pyridinyl.

Scheme 1

Design of the title compounds.

Scheme 2

Synthesis of the title compounds.

Figure 1

X-ray crystal structure of 5a18 (CCDC2015868).

Figure 2

The predicted binding modes of 5a4, 5b2 and difenoconazole with CYP51. The protein was shown as cartoon, 5a4, 5b2 and difenoconazole were shown as magenta, cyan and green sticks, respectively.

Figure 3

Schematic diagram showed the hydrophobic interactions (shown as starbursts) and H-bond interactions (denoted by dotted green lines) and π-π stacking of three compounds with CYP51. (A) Schematic diagram showed the hydrophobic interactions, H-bond interactions and π-π stacking of 5a4 with CYP51; (B) Schematic diagram showed the hydrophobic interactions and π-π stacking of 5b2 with CYP51; (C) Schematic diagram showed the hydrophobic interactions difenoconazole with CYP51.