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Pocket-based Lead Optimization Strategy for the Design and Synthesis of Chitinase Inhibitors
- Dong, Yawen, Hu, Song, Jiang, Xi, Liu, Tian, Ling, Yun, He, Xiongkui, Yang, Qing, Zhang, Li
- Journal of agricultural and food chemistry 2019 v.67 no.13 pp. 3575-3582
- Ostrinia furnacalis, amino acids, chitinase, derivatization, enzyme inhibition, enzyme inhibitors, insect pests, molting, pest control, pesticides, structure-activity relationships
- Insect chitinases play an indispensable role in shedding old cuticle during molting. Targeting chitinase inhibition is a promising pest control strategy. Of ChtI, a chitinase from the destructive insect pest Ostrinia furnacalis (Asian corn borer), has been suggested as a potential target for designing green pesticides. A 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate scaffold was previously obtained, and further derivatization generated the lead compound 1 as Of ChtI inhibitor. Here, based on the predicted binding mode of compound 1, the pocket-based lead optimization strategy was applied. A series of analogues was synthesized, and their inhibitory activities against Of ChtI were evaluated. Compound 8 with 6-tert-pentyl showed preferential inhibitory activity with a Kᵢ value of 0.71 μM. Their structure–activity relationships suggested that the compound with larger steric hindrance at the 6-nonpolar group was essential for inhibitory activity due to its stronger interactions with surrounding amino acids. This work provides a strategy for designing potential chitinase inhibitors.