Design, Synthesis, and Insecticidal Activity of Novel Doramectin Derivatives Containing Acylurea and Acylthiourea Based on Hydrogen Bonding

Abstract

Our recent investigation on the insecticidal activities of several doramectin derivatives preliminarily revealed that the presence of hydrogen bonds at the C4″ position of the molecule with target protein γ-aminobutyric acid (GABA) receptor was crucial for retaining high insecticidal activity. As a continuation of our research work on the development of new insecticides, two series of novel acylurea and acylthiourea doramectin derivatives were designed and synthesized. The bioassay results indicated that the newly synthesized compounds (5o, 5t, and 6t) exhibited higher insecticidal activity against diamondback moth, oriental armyworm, and corn borer than the control compounds doramectin, commercial avermectins, chlorbenzuron, and lead compound 3g in our laboratory. Specifically, compound 5t was identified as the most promising insecticide against diamondback moth, with a final mortality rate of 80.00% at the low concentration of 12.50 mg/L, showing approximately 7.75-fold higher potency than the parent doramectin (LC50 value of 48.1547 mg/L), 6.52-fold higher potency than commercial avermectins (LC50 value of 40.5507 mg/L), and 3.98-fold higher potency than compound 3g (LC50 value of 24.7742 mg/L). Additionally, molecular docking simulations revealed that compound 5t (2.17, 2.20, 2.56, and 2.83 Å) displayed stronger hydrogen-bond action in binding with the GABA receptor, better than that of compound 5o (1.64 and 2.15 Å) and compound 6t (2.20 and 2.31 Å) at the C4″ position. This work demonstrated that these compounds containing hydrogen-bond groups might contribute to the improvement of insecticidal activity and supply certain hints toward structure optimization design for the development of new insecticides.

Design, Synthesis, and Mechanism of Antiviral Acylurea Derivatives Containing a Trifluoromethylpyridine Moiety

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.1c03586. Physical characteristics and 1 H, 13 C, and 19 F NMR spectra of the title compounds (7a−7ab) (PDF)…”

“…14−16 The importance of hydrogen bonding between bioactive molecules and target proteins has been widely demonstrated. 17,18 Thus, with the urea bridge being conserved, many modifications of the acyl and heterocyclic aryl moieties have resulted in rich biological activities for controlling insects, 19 fungi, 20 cancers, 21 tumors, 16 etc. The combination of urea and acyl groups remains a priority target for the creation of new agrochemicals.…”

“… Most acylurea derivatives contain a common three-part molecular skeleton: an acyl moiety, urea bridge, and heterocyclic aryl ring (Figure ). The urea bridge contains two NH groups that easily engage in hydrogen bonding to target proteins. − The importance of hydrogen bonding between bioactive molecules and target proteins has been widely demonstrated. , Thus, with the urea bridge being conserved, many modifications of the acyl and heterocyclic aryl moieties have resulted in rich biological activities for controlling insects, fungi, cancers, tumors, etc. The combination of urea and acyl groups remains a priority target for the creation of new agrochemicals.…”

Recent trends in chemistry, structure, and various applications of 1-acyl-3-substituted thioureas: a detailed review

“…Zhang et al 90 synthesized and characterized a novel series of acyl thiourea derivatives of doramectin 112a–v Scheme 48 . Their biological assay and molecular docking studies showed them to be used as potential insecticides.…”

High Value Utilization of an Avermectin Fermentation Byproduct: Novel B2a Derivatives as Pesticide Candidates

“…Avermectins , represent a group of 16-membered macrolide lactones obtained by fermentation from Streptomyces avermitilis. , These compounds are generally used as a pesticide for the treatment of insect pests and parasitic worms due to their anthelmintic and insecticidal properties. , The main mechanism of avermectins is acting on γ-aminobutyric acid (GABA)-related chloride ion channels , unique to nematodes, insects, ticks, and arachnids. Owing to their remarkable biological activity − and low mammalian toxicity, avermectins, also called natural product pesticides, have long been studied for commercial agricultural use around the globe, with China being the world’s largest producer of avermectins. Since their discovery, various studies , have been conducted to obtain novel derivatives with higher activity and lower toxicity by modifying avermectin B1a species such as ivermectin, emamectin benzoate, and selamectin (Figure ).…”