Redevelopment of limonoid as potential pesticidal resource from non-edible wastes of the citrus industry: Combinatorial synthesis and insecticidal evaluation of limonin-derived oxime ethers with scaffold diversity

Plant natural products provide considerable resources for the innovation of agrochemicals or pharmaceuticals due to their extensive biological potential and scaffold diversity. Limonin , a naturally occurring tetracyclic triterpenoid found in non-edible wastes of the citrus industry is a promising lead for developing new pesticide candidates. Reported herein is the limonin-directed analogues with scaffold diversity and their agricultural insecticidal activity evaluation. Pesticidal bioassay results revealed that 29 target compounds displayed varying degrees of enhanced larvicidal activity against Plutella xylostella Linnaeus compared to their precursor limonin. Among them, compounds IIId , Vd , VIb , VId , VIIa , VIId , and VIIf exhibited more pronounced insecticidal potential with LC 50 values of 6.97, 10.07, 13.50, 13.74, 7.43, 8.63, and 12.82 μg/mL, respectively, far exceeding that of limonin (LC 50 = 110.67 μg/mL) and the two positive controls rotenone (LC 50 = 33.29 μg/mL) and toosendanin (LC 50 = 31.60 μg/mL). Notably, the larvicidal activity of IIId , VIIa , and VIId against P. xylostella was greater than 15.8-, 14.8-, and 12.8-fold that of limonin, respectively. This project also disclosed that 27 target compounds demonstrated insecticidal activity against Mythimna separata Walker superior to limonin. Compounds IIIa , IIIc , IIIf , Vd , VIa , and VIId showed potent growth inhibitory activity against M. separata with LC 50 values of 0.63, 0.42, 0.51, 0.69, 0.43, and 0.71 mg/mL, respectively, whereas the LC 50 value of limonin was 1.20 mg/mL. It was illustrated that these heterocyclic scaffolds played an important role in improving the insecticidal performance of limonin. Further cytotoxicity assay indicated that the tested compounds showed almost no cytotoxicity to human keratinocyte cell line (HaCaT), thus showing a good safety profile. Overall, this work will provide valuable insight into agrochemical innovation based on limonin and will also promote the industrial value of limonoids from citrus industrial wastes. • Limonin-type oxime ether derivatives with scaffold diversity were constructed by a combinatorial synthesis strategy. • Compounds IIId , Vd , VIb , VId , VIIa , VIId , and VIIf were found to be potent against Plutella xylostella Linnaeus. • Analogues IIIa , IIIc , IIIf , Vd , VIa , and VIId exhibited pronounced insecticidal activity against Mythimna separata Walker. • The results will be beneficial for promoting the redevelopment and utilization of citrus industrial wastes.