Design and Synthesis of Novel Indole-Derived -Methylcarbamoylguanidinyl Chitinase Inhibitors with Significantly Improved Insecticidal Activity.

Chitinases play an important role in the molting process of insects and are potential targets for the development of green insecticides. Based on the feature that the +1/+2 sites in ChtI, ChtII, and Chi-h have tryptophan residues in mismatch-parallel position, a strategy to introduce indole scaffold into chitinase inhibitors was proposed, and multitarget chitinase inhibitors containing -methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound exhibited significant inhibitory activity against ChtI, ChtII, and Chi-h, with IC values of 0.7, 0.79, and 0.58 μM, and values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 μM, respectively. insecticidal activity showed that compounds and exhibited excellent insecticidal activity against and , with LC values of 0.79 and 9.17 mg/L against , respectively, and 3.58 and 83.09 mg/L against , respectively, making them the most potent chitinase inhibitors with insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that -methylcarbamoylguanidinyl binds to the -1 catalytic site, while additional interactions acquired by π-π stacking and hydrophobic interactions of the indole scaffold with tryptophan increase the binding affinity of the targets to chitinases. This work provides a new direction for the development of chitinase inhibitors with compounds and potentially serving as promising candidates for pesticide development.