Rational Design, Synthesis, and Biological Investigations of <i>N</i>-Methylcarbamoylguanidinyl Azamacrolides as a Novel Chitinase Inhibitor

Abstract

Chitinase is one of the most important glycoside hydrolyases, widely existing in bacteria, fungi, insects, and plants. It is involved in fungal cell wall remodeling and insect molting. Chitinase inhibitors are an effective means of controlling pathogens and pests. Natural product argifin is a 17-membered pentapeptide that exhibits efficient chitinase inhibitory activity. However, the complexity of the synthetic process results in a lot of restrictions for wide range of applications. In this work, we designed a series of azamacrolide chitinase inhibitors based on the structural features of argifin that have high inhibitory activities against bacterial and insectile chitinase. The most potent chitinase inhibitor compound <b>19c</b> exhibited IC₅₀ values of 56 nM and 110 nM against <i>Of</i>Chi-h and <i>Sm</i>ChiB, respectively. The molecular docking and molecular dynamics simulations revealed that all inhibitors were bound to the -1 subsite of chitinases via <i>N</i>-methylcarbamoylguanidinyl as well as argifin. Finally, a bioactivity assay against pests was carried out. Compound <b>18a</b> showed 80% mortality for <i>Mythimna separata</i> at a concentration of 50 mg/L. Besides, insecticides <b>19b</b> and <b>19c</b> exhibited high mortality against <i>Plutella xylostella</i> (76 and 73% mortalities at 50 mg/L, respectively).