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

Authors :
Li F
Chen W
Ai Y
Zhou X
Xiang J
Lu H
Dong Y
Yang Q
Zhang J
Source :
Journal of agricultural and food chemistry [J Agric Food Chem] 2024 Oct 02; Vol. 72 (39), pp. 21410-21418. Date of Electronic Publication: 2024 Sep 18.
Publication Year :
2024

Abstract

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 Of ChtI, Of ChtII, and Of 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 N -methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound 8u exhibited significant inhibitory activity against Of ChtI, Of ChtII, and Of Chi-h, with IC <subscript>50</subscript> values of 0.7, 0.79, and 0.58 μM, and K <subscript> i </subscript> values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 μM, respectively. In vivo insecticidal activity showed that compounds 8a and 8g exhibited excellent insecticidal activity against Plutella xylostella and Mythimna separata , with LC <subscript>50</subscript> values of 0.79 and 9.17 mg/L against P. xylostella , respectively, and 3.58 and 83.09 mg/L against M. separata , respectively, making them the most potent chitinase inhibitors with in vivo insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that N -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 8a and 8g potentially serving as promising candidates for pesticide development.

Details

Language :
English
ISSN :
1520-5118
Volume :
72
Issue :
39
Database :
MEDLINE
Journal :
Journal of agricultural and food chemistry
Publication Type :
Academic Journal
Accession number :
39291429
Full Text :
https://doi.org/10.1021/acs.jafc.4c03536