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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.