Investigation of the Antifungal Activity and Preliminary Mode of Action of Novel 2-(1H-Indol-2-yl)-1,3,4-oxadiazole Derivatives against Botrytis cinerea

The discovery of novel leads and new targets is an important approach to address the issue of fungicide resistance by new fungicide development. The indole skeleton has been widely utilized in agrochemicals due to its unique biological activity. YZK-C22 is a potent pyruvate kinase inhibitor with high antifungal activity. Several novel fungicide leads were developed based on YZK-C22. Inspired by these, the [1,2,4]triazino[4,5-a]indol-1(2H)-one derivatives were designed using a skeleton hopping strategy; however, these compounds exhibited moderate fungicidal activity. Unexpectedly, 2-(1H-indol-2-yl)-1,3,4-oxadiazole derivatives formed under controlled reaction conditions showed significantly higher fungicidal activity. Compounds 6c, 6d, 6f, and 6j exhibited excellent antifungal activity in vitro, with EC50 values ranging from 0.120 to 0.310 μg/mL against Botrytis cinerea, more potent than commercial fungicide pyrimethanil (EC50 = 0.990 μg/mL). In the field trials at 540 and 720 g of active ingredient (ai)/hm2, compound 6c exhibited 81.46 and 86.58% efficacy against B. cinerea, higher than that of pyrimethanil at a rate of 540 g of ai/hm2 (70.46%). The affinity constants of compounds 6c and 6d to pyruvate kinase from B. cinerea were lower than that of YZK-C22. Higher field efficacy but lower affinity to pyruvate kinase implies that these compounds may work as prodrugs or have a different mode of action. Thus, 2-(1H-indol-2-yl)-1,3,4-oxadiazole derivatives are worth being further investigated.