Glycosyl structure guided design, synthesis and biological accessment of chitin degrading enzyme inhibitors with insecticidal activity

Abstract

The synergistic action of GH18 chitinase and GH20 β−N−acetylhexosaminidase (Hex), two glycosylated hydrolase families, is crucial in the molting process of the Asian corn borer (Ostrinia furnacalis) and are regarded as important target for the development of green pesticides. Herein, two series of compounds A (15 compounds) and B (14 compounds) were synthesized to inhibit chitin degrading enzyme by the strategy of the multitarget. Enzyme activity experiments showed that the enzyme activity of B−series compounds was superior to A−series compounds, attributing to the strong hydrogen bond interaction between Glu328 and 1,3,4 thiadiazoline as well as hydrophilicity of 1,3,4 thiadiazoline. Thereinto, B12 was shown to exhibit inhibitory activities against all four chitinolytic enzymes as C−glycoside thiadiazole inhibitors with K_i of 23.21 μM, 40.20 μM, 28.32 μM and 15.21 μM for OfChtI, OfChtII, OfChi−h and OfHex1, respectively, and possessed a favourable insecticidal activity (∼70 %) against P. xylostella and O.furnacalis. What's more, the hydrophobic effect and polar interaction played significant roles in the combination between B12 with OfHex1. Particularly, preliminary biological tests revealed that B12 possessed certain inhibitory effect on the growth and development of O.furnacalis and P. xylostella. This study provides an example of using a multitarget strategy to develop C−glycoside thiadiazole as an insecticide precursor for the biodegradation of chitin.