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. 2021 Oct 25:9:757584.
doi: 10.3389/fchem.2021.757584. eCollection 2021.

Synthesis, 3D-QSAR and Molecular Docking Study of Nopol-Based 1,2,4-Triazole-Thioether Compounds as Potential Antifungal Agents

Xiu Wang  1 , Wengui Duan  1 , Guishan Lin  1 , Baoyu Li  1 , Ming Chen  1 , Fuhou Lei  2
Affiliations

Synthesis, 3D-QSAR and Molecular Docking Study of Nopol-Based 1,2,4-Triazole-Thioether Compounds as Potential Antifungal Agents

Xiu Wang et al. Front Chem. .

Abstract

Cytochrome bc 1 complex is an important component of cellular respiratory chain, and it is also an important target enzyme to inhibit the growth of plant pathogens. Using cytochrome bc 1 complex as the target enzyme, twenty-three novel nopol-based 1,2,4-triazole-thioether compounds were designed and synthesized from natural preponderant resource β-pinene, and their structures were confirmed by FT-IR, NMR, ESI-MS and elemental analysis. The in vitro antifungal activity of the target compounds 5a-5w was preliminarily evaluated against eight plant pathogens at the concentration of 50 µg/ml. The bioassay results showed that the target compounds exhibited the best antifungal activity against Physalospora piricola, in which compounds 5b (R= o-CH3 Ph), 5e (R= o-OCH3 Ph), 5h (R= o-F Ph), 5m (R= o-Br Ph), 5o (R= m,m-OCH3 Ph), and 5r (R= p-OH Ph) had inhibition rates of 91.4, 83.3, 86.7, 83.8, 91.4 and 87.3%, respectively, much better than that of the positive control chlorothalonil. Also, compound 5a (R= Ph) had inhibition rate of 87.9% against Rhizoeotnia solani, and compound 5b (R= o-CH3 Ph) had inhibition rates of 87.6 and 89% against Bipolaris maydis and Colleterichum orbicala, respectively. In order to develop novel and promising antifungal compounds against P. piricola, the analysis of three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method on the basis of their antifungal activity data, and a reasonable and effective 3D-QSAR model (r 2 = 0.944, q 2 = 0.685) has been established. In addition, the theoretical study of molecular docking revealed that the target compounds could bind to and interact with the site of cytochrome bc 1 complex.

Keywords: 1, 2, 4-triazole-thioether; 3D-QSAR; molecular docking; nopol; β-pinene.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The asterisk skeleton of title compounds.
FIGURE 2
FIGURE 2
Superposed mode of the compounds.
SCHEME 1
SCHEME 1
Synthesis of nopol-based 1,2,4-triazole-thioether compounds 5a-5w.
FIGURE 3
FIGURE 3
The experimental and predicted AF values.
FIGURE 4
FIGURE 4
(A) Contours of steric contribution: green contour favors steric or bulky group, yellow contour denotes disfavored region. (B) Contours of electrostatic contribution: blue contour indicates electropositive charge, red contour electronegative charge.
FIGURE 5
FIGURE 5
The proposed new molecules of 2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2yl)ethyl 2-((4-methyl-5-(3-(methyl(neopentyl)amino)phenyl)-4H-1,2,4-triazol-3-yl)thio)acetate (A);2-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2yl)ethyl 2-((5-(3-(isobutyl(propyl)amino)phenyl)-4-methyl-4H-1,2,4-triazol-3-yl)thio)acetate (B).
FIGURE 6
FIGURE 6
20 Docked conformations cluster for compound 5b.
FIGURE 7
FIGURE 7
Monotonicity of binding energies versus AF values for the title compounds.
FIGURE 8
FIGURE 8
(A1) The molecular docking of compound azoxystrobin with cytochrome bc 1 complex. (A2) The binding conformation of compound azoxystrobin in the active site of cytochrome bc 1 complex. (A3) The 2D interactions mao of compound azoxystrobin with cytochrome bc 1 complex. (A4) The 3D interactions map of compound azoxystrobin with cytochrome bc 1 complex.
FIGURE 9
FIGURE 9
(B1) The molecular docking of compound 5b with cytochrome bc 1 complex. (B2) The binding conformation of copound 5b in the active site of cytochrome bc 1 complex. (B3) The 2D interactions map of compound 5b with cytochrome bc 1 complex. (B4) The 3D interactions map of compound 5b with cytochrome bc 1 complex.
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