Rational Design, Synthesis, and Biological Investigations of N-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 19c exhibited IC 50 values of 56 nM and 110 nM against Of Chi-h and SmChiB, respectively. The molecular docking and molecular dynamics simulations revealed that all inhibitors were bound to the −1 subsite of chitinases via N-methylcarbamoylguanidinyl as well as argifin. Finally, a bioactivity assay against pests was carried out. Compound 18a showed 80% mortality for Mythimna separata at a concentration of 50 mg/L. Besides, insecticides 19b and 19c exhibited high mortality against Plutella xylostella (76 and 73% mortalities at 50 mg/L, respectively).

Rational Design of N-Methylcarbamoylguanidinyl Derivatives as Highly Potent Dual-Target Chitin Hydrolase Inhibitors for Retarding Growth of Pest Insects

“…The compound N -( tert -butoxycarbonyl)- S -methylisothiourea 2 was prepared, according to the reported methods . Then, compound 3 was obtained by our previous report . Compound 4 was obtained, according to the following procedure.…”

Design, synthesis, and insecticidal activity evaluation of piperine derivatives

“…Plutella xylostella , also known as “dangling silkworm” or “diamondback moth,” is a pest commonly found on vegetables, causing damage by larvae feeding on the leaves of cruciferous vegetables. In recent years, the damage of Plutella xylostella has become increasingly serious, with significant adverse effects on the yield and quality of cruciferous vegetables ( Wang et al, 2011 ; Zhao et al, 2022 ). The primary commercial agents used to control Plutella xylostella are traditional insecticides such as emamectin.…”

Discovery of Azo-Aminopyrimidines as Novel and Potent Chitinase OfChi-h Inhibitors via Structure-Based Virtual Screening and Rational Lead Optimization

“…A number of small molecule inhibitors against O f Chi-h have been reported to date, including chitoheptaose, rhodanine derivatives, TMG-(GlcNAc) 4 , , phlegmacin B 1 , polonimides A–C, berberines, thiazolylhydrazones, deoxyshikonin, azamacrolides, lynamicin B and dipyrido-pyrimidines , (Figure ). However, the application of these inhibitors is limited by their complicated synthesis processes or their poor physicochemical properties. , Thus, more studies need to be carried out to develop potent and easily synthesizable O f Chi-h inhibitors with suitable pesticide-like properties.…”

“…11 These crystallographic investigations on Of Chi-h have laid a solid foundation for the discovery of novel and potent inhibitors via in silico analysis. 7 A number of small molecule inhibitors against Of Chi-h have been reported to date, including chitoheptaose, 11 rhodanine derivatives, 12 TMG-(GlcNAc) 4 , 11,13 phlegmacin B 1 , 14 poloni-mides A−C, 15 berberines, 16 thiazolylhydrazones, 17 deoxyshikonin, 10 azamacrolides, 18 lynamicin B 19 and dipyrido-pyrimidines 20,21 (Figure 1). However, the application of these inhibitors is limited by their complicated synthesis processes or their poor physicochemical properties.…”