Novel 1,3,4-Oxadiazole-2-carbohydrazides as Prospective Agricultural Antifungal Agents Potentially Targeting Succinate Dehydrogenase

• Published in: Journal of agricultural and food chemistry 2019-12, Vol.67 (50), p.13892-13903
• Main Authors: Wu, Yuan-Yuan, Shao, Wu-Bin, Zhu, Jian-Jun, Long, Zhou-Qing, Liu, Li-Wei, Wang, Pei-Yi, Li, Zhong, Yang, Song
• Format: Article
• Language: English
• Subjects: Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - chemistry; Fungicides, Industrial - chemistry; Fungicides, Industrial - pharmacology; Fusarium - drug effects; Fusarium - enzymology; Hydrazines - chemistry; Hydrazines - pharmacology; Molecular Docking Simulation; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Plant Diseases - microbiology; Plant Diseases - prevention & control; Structure-Activity Relationship; Succinate Dehydrogenase - antagonists & inhibitors; Succinate Dehydrogenase - chemistry
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.9b05942

A novel simple 1,3,4-oxadiazole-2-carbohydrazide was reported to discover low-cost and versatile antifungal agents. Bioassay results suggested that a majority of the designed compounds were extremely bioactive against four types of fungi and two kinds of oomycetes. This extreme bioactivity was highlighted by the applausive inhibitory effects of compounds 4b, 4h, 5c, 5g, 5h, 5i, 5m, 5p, 5t, and 5v against Gibberella zeae, affording EC50 values ranging from 0.486 to 0.799 μg/mL, which were superior to that of fluopyram (2.96 μg/mL) and comparable to those of carbendazim (0.947 μg/mL) and prochloraz (0.570 μg/mL). Meanwhile, compounds 4g, 5f, 5i, and 5t showed significant actions against Fusarium oxysporum with EC50 values of 0.652, 0.706, 0.813, and 0.925 μg/mL, respectively. Pharmacophore exploration suggested that the N′-phenyl-1,3,4-oxadiazole-2-carbohydrazide pattern is necessary for the bioactivity. Molecular docking of 5h with succinate dehydrogenase (SDH) indicated that it can completely locate the inside of the binding pocket via hydrogen-bonding and hydrophobic interactions, revealing that this novel framework might target SDH. This result was further verified by the significant inhibitory effect on SDH activity. In addition, scanning electron microscopy patterns were performed to elucidate the anti-G. zeae mechanism. Given these features, this type of framework is a suitable template for future exploration of alternative SDH inhibitors against plant microbial infections.