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

Abstract

Chitinase OfChi-h, from the destructive agricultural pest Ostrinia furnacalis, is considered as a promising target for green pest control and management. In this study, structure-based virtual screening and rational molecular optimization led to the synthesis of a series of azo-aminopyrimidine derivatives as a novel class of OfChi-h inhibitors. Among them, the most potent compound 8f, with a benzyl on the amino group at the 4-position of pyrimidine, exhibited a K i value of 64.7 nM against OfChi-h. In addition, molecular docking studies were carried out to investigate the basis for the potency of the aminopyrimidines against OfChi-h. Furthermore, the insecticidal activity of the target compounds against Plutella xylostella and Ostrinia nubilalis was assessed, and the potent OfChi-h inhibitors 8f and 8i showed higher insecticidal activity than the control pesticide hexaflumuron. The present work revealed that the azo-aminopyrimidine skeletons characterized by concise chemical structure and high efficiency could be further developed as potential pesticides for the control of lepidopteran pests.

Group h Chitinase: A Molecular Target for the Development of Lepidopteran-Specific Insecticides

“…A series of azoaminopyrimidine derivatives was designed and synthesized as a novel class of Of Chi-h inhibitors via virtual screening and rational molecular optimization. 36 The most potent compound 2a, with benzyl on the amino group at the 4 position of pyrimidine, displayed a K i value of 0.0647 μM toward Of Chi-h (Figure 4 and Table 1).…”

Discovery of Potent N-Methylcarbamoylguanidino Insect Growth Regulators Targeting OfChtI and OfChi-h

“…Recently, some small-molecule Chitinase inhibitors with planar structures, such as phlegmacin B 1 , azo-aminopyrimidines, and dipyrido-pyrimidine derivatives, have been reported (Figure A). − The binding modes revealed that these potent Chitinase inhibitors located at the reducing end (+1 and +2 subsites) and formed π–π stacking interactions with aromatic tryptophan residues. The Chitinase inhibitory mechanism indicates that an aromatic plane is more suitable for the substrate binding groove of Chitinase .…”

Identification of Triazolo-quinazolinone Derivatives as Novel and Potent Chitinase OfChi-h Inhibitors Based on Structure-Based Virtual Screening

“…These crystallographic studies of Of Chi-h lay a solid foundation for the design and discovery of structure-based novel inhibitors. 10 In view of the importance of Of Chi-h, several inhibitors with different chemical structures have been reported to date, such as chitoheptaose, 10 TMG-(GlcNAc) 4 , 10,12 phlegmacin B 1 , 13 dipyrido-pyrimidines, 14,15 azo-aminopyrimidines, 16 berberines, 17 rhodanines, 18 methylcarbamoyl-guanidines, 19,20 thiazolylhydrazones, 21 deoxyshikonin, 22 polonimides, 23 lynamicin B, 24 and SN-38 25 (Figure 1). However, many of the reported inhibitors (especially glycosyl-based inhibitors) have limita-tions in poor physicochemical properties and complicated synthesis processes.…”

“…However, many of the reported inhibitors (especially glycosyl-based inhibitors) have limita-tions in poor physicochemical properties and complicated synthesis processes. 16,17 Thus, the focus of the present study is to develop a type of novel and potent Of Chi-h inhibitor with a concise structure and suitable pesticide-like properties.…”

“…In view of the importance of Of Chi-h, several inhibitors with different chemical structures have been reported to date, such as chitoheptaose, TMG-(GlcNAc) 4 , , phlegmacin B 1 , dipyrido-pyrimidines, , azo-aminopyrimidines, berberines, rhodanines, methylcarbamoyl-guanidines, , thiazolylhydrazones, deoxyshikonin, polonimides, lynamicin B, and SN-38 (Figure ). However, many of the reported inhibitors (especially glycosyl-based inhibitors) have limitations in poor physicochemical properties and complicated synthesis processes. , Thus, the focus of the present study is to develop a type of novel and potent Of Chi-h inhibitor with a concise structure and suitable pesticide-like properties.…”