Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo

Abstract

To develop new compounds with high activity, broad spectrum and low-toxicity, 17 benzamides substituted with quinoline-linked 1,2,4-oxadiazole were designed using the splicing principle of active substructures and were synthesized. The biological activities were evaluated against 10 fungi, indicating that some of the synthetic compounds showed excellent fungicidal activities. For example, at 50 mg/L, the inhibitory activity of 13p (3-Cl-4-Cl substituted, 86.1%) against Sclerotinia sclerotiorum was superior to that of quinoxyfen (77.8%), and the inhibitory activity of 13f (3-CF3 substituted, 77.8%) was comparable to that of quinoxyfen. The fungicidal activities of 13f and 13p to Sclerotinia sclerotiorum were better than that of quinoxyfen (14.19 mg/L), with EC50 of 6.67 mg/L and 5.17 mg/L, respectively. Furthermore, the acute toxicity of 13p was 19.42 mg/L, classifying it as a low-toxic compound.

Chemical representation learning for toxicity prediction

“…Some of these fragments can be linked to tremendous recent literature, for example bit 388 corresponds to a 1,2,4-oxadiazole ring. 1,2,4-Oxadiazole-derivatives have been largely neglected by medicinal chemistry until 2005, but in the past 15 years, research has grown exponentially 113 and only in 2022 researchers reported cytotoxic, 114 fungicidal, 115 anti-inflammatory, 114 antiparasitary and antiproliferative 116 effects of 1,2,4-oxadiazole derivatives.…”

1,2,4-Oxadiazole as a potential scaffold in agrochemistry: a review

“…Similar observations were obtained in the design of quinoline-linked 1,2,4-oxadiazoles, where the quinoline moiety of the target compounds originated from the fungicide quinoxyfen. 75 Among them, compounds 54 and 55 had the highest efficacy against S. sclerotiorum with the EC 50 values of 6.67 mg L −1 and 5.17 mg L −1 , respectively, surpassing that of the standard quinoxyfen. In addition, compound 55 demonstrated low effects on zebrafish embryos with an acute toxicity value of 19.42 mg L −1 .…”

Quinoline Derivatives in Discovery and Development of Pesticides

“…76 In addition, compound 9 containing flexible aryl ether had an EC 50 of 5.17 mg/L against S. sclerotiorum. 77 This may imply that the introduction of the diaryl ether structure in this scaffold structure is more favorable to enhance the fungicidal activity of the compounds.…”