Design, Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Quinoxaline-2-Oxyacetate Hydrazide

Abstract

Plant pathogenic fungi pose a major threat to global food security, ecosystem services, and human livelihoods. Effective and broad-spectrum fungicides are needed to combat these pathogens. In this study, a novel antifungal 2-oxyacetate hydrazide quinoxaline scaffold as a simple analogue was designed and synthesized. Their antifungal activities were evaluated against Botrytis cinerea (B. cinerea), Altemaria solani (A. solani), Gibberella zeae (G. zeae), Rhizoctonia solani (R. solani), Colletotrichum orbiculare (C. orbiculare), and Alternaria alternata (A. alternata). These results demonstrated that most compounds exhibited remarkable inhibitory activities and possessed better efficacy than ridylbacterin, such as compound 15 (EC₅₀ = 0.87 μg/mL against G. zeae, EC₅₀ = 1.01 μg/mL against C. orbiculare) and compound 1 (EC₅₀ = 1.54 μg/mL against A. alternata, EC₅₀ = 0.20 μg/mL against R. solani). The 3D-QSAR analysis of quinoxaline-2-oxyacetate hydrazide derivatives has provided new insights into the design and optimization of novel antifungal drug molecules based on quinoxaline.

Keywords: 2-oxyacetate hydrazide; 3D-QSAR; antifungal activity; quinoxaline.

Figure 1

Design strategy of title compounds [31].

Figure 2

The synthetic route of the target compounds. Reagents and conditions. (i) H₂O, SDS; (ii) POCl₃, reflux; (iii) CsCO₃, DMSO, 80 °C, 5 h; (iv) NaOH, H₂O, rt; HCl, H₂O, rt; and (v) TBTU, Et₃N, CH₃CN. (a–e) are reaction intermediate.

Figure 3

The in vivo preventive effects of compound 2 against R. solani and compound 6 against B. cinerea.

Figure 4

SEM images of R. solani hyphae treated by DMSO (A–C) and 2 (D–I).

Figure 5

Template compound 28 (A) and composite renderings (B).

Figure 6

Experimental and predicted values of CoMFA (A) and CoMSIA (B) models pEC₅₀.

Figure 7

CoMFA (A,B) contour maps and CoMSIA (C–F) contour maps with compound 28 shown inside fields. Green and yellow modules indicate regions where steric bulk would increase and reduce anti-R. solani activity; blue and red modules indicate regions where electropositive and electronegative groups would increase anti-R. solani activity; yellow and grey modules indicate regions where hydrophobicity and hydrophilicity would increase anti-R. solani activity; magenta and red modules indicate regions where H-bond acceptor groups would increase and reduce the anti-R. solani activity, meanwhile, cyan and purple modules indicate regions where H-donor groups would increase and reduce anti-R. solani activity.