3D-QSAR-Based Molecular Design to Discover Ultrahigh Active N-Phenylpyrazoles as Insecticide Candidates

Abstract

Three-dimensional quantitative structure−activity relationship (3D-QSAR) is one of the most important and effective tools to direct molecular design in new pesticide development. Chlorantraniliprole is an anthranilic diamide ryanodine receptor (RyR) agonist with ultrahigh activity, high selectivity, and mammalian safety. To continue our studies on new insecticide development, here, we designed new insecticidal N-phenylpyrazoles by using 3D-QSAR of chlorantraniliprole analogues as a guide. Most of the target compounds synthesized exhibited medium to excellent activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Compounds III b and III y showed similar activity against M. separata as chlorantraniliprole (LC 50 values: 0.21, 0.25, and 0.16 μg mL −1 respectively). Compounds III b exhibited a 3-fold higher potency against P. xylostella than chlorantraniliprole. For S. frugiperda, the potency of III a and III b was 2.9 and 2.0 times higher than that of the positive control, respectively. The mode of action of the title compounds was validated by calcium imaging experiments and molecular docking using their target RyRs. III b can dock well with mutated P. xylostella RyRs, implying a potentially lower cross-resistance risk as compared with commercial RyR agonists. Density functional theory calculations suggested the feasibility of higher potency with the structural modifications. Compound III b was found to be an ultrahigh active insecticidal candidate with a broad spectrum for integrated pest management.

Discovery of Trisubstituted N-Phenylpyrazole Containing Diamides with Improved Insecticidal Activity

“…The representative compound IV p with the best insecticidal activity against P. xylostella was docked with P. xylostella RyR to further explain the action site of target compounds referring to our previous methods. , As shown in Figure , chlorantraniliprole formed three hydrogen bonds with amino acid residues ASP4942, TYR4922, and LYS4700, and there were also two π–π stackings between the phenyl ring and TYR4922 as well as the pyridine ring and TYR4697. Compared with chlorantraniliprole, although only one hydrogen bond was formed between compound IV p and residue TYR4697, the binding between IV p and the receptor was much stronger than that of chlorantraniliprole.…”

“…The synthesis route of 7i−7l followed the synthesis method of 7e−7h (Figure 2). According to our previous literature, 22 7a− 7l were hydrolyzed by lithium hydroxide and then subjected to an acyl chloride method with intermediate 9 to obtain IV a− IV ah (Figure 2). Biological Activity Assay.…”

“…20−23 The design of ultrahigh-active compounds based on a three-dimensional quantitative structure−activity relationship (3D-QSAR) model had also been proven to be a significant molecular design strategy in our previous studies. 22,24,25 Guided by these methods, the development of insecticides tends to not only have high biological activity but also show good competitiveness. On the basis of summarizing our previous 3D-QSAR model and molecular structures synthesized (Figures S1 and S2), 20−24 chlorine atom at position 2, a less steric and weaker electronwithdrawing fluorine atom at position 4, and an electronwithdrawing substituent at position 5 of the phenyl ring would benefit insecticidal activity.…”

CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4-b][1,3,4]-thiadizoles

“…Natural products have many favorable properties such as ecological compatibility, diversity of structures, unique mode of action, good biological performance, and low risk of cross resistance. − Bioactive natural products and their metabolites can be ideal lead compounds for structure optimization. Typical agrochemicals from natural products include derivatives of strobilurins, coumarins, psoralen, pyrethrin, neopeltolide, nicotine, luotonin A, and rotenone − The principle of IDM is to fully consider cost of raw materials and intermediates, sustainability, facile industrialization, and freedom to operate in order to create novel bioactive molecules. Several rounds of “design–synthesis–test–analysis” are usually needed to reach targets with novel structures and reasonable biological performance. ,− Commercial pesticides such as coumoxystrobin, pyraoxystrobin, pyrimidifen, diflumetorim, and flufenerim are examples from IDM strategy. , PFVS is realized through biophysical screening via analyzing interactions between a target protein and its ligand .…”

Discovery of Novel Diamides Scaffold Containing Monofluoro-acrylamides Activating the Insect Ryanodine Receptor

“…RyR in insects is very different from that in mammals and has been verified to be the target of diamide insecticides . The anthranilic diamides represented by chlorantraniliprole (CHL) are the most significant class of insecticides to reduce losses caused by Lepidoptera and Coleoptera agricultural pests. , Since the diamide insecticides were commercialized, a huge market success (annual sales > USD 2.3 billion) has been witnessed, and the research on diamide insecticides continues to attract companies and research institutions. − Insecticides acting on this target do not have cross-resistance with other commonly used insecticides . However, due to its excellent control efficacy, the widespread and frequent use of diamide insecticide around the world has led to the emergence of resistance in some districts. − …”