3D-QSAR Directed Discovery of Novel Halogenated Phenyl 3-Trifluoroethoxypyrazole Containing Ultrahigh Active Insecticidal Anthranilic Diamides

Abstract

Pests are one of the major factors causing crop damage and food security problems worldwide. Based on our previous studies on the discovery of insecticidal leads targeting the ryanodine receptors (RyRs), a three-dimensional quantitative structure− activity relationship (3D-QSAR) model was established to design and synthesize a series of anthranilic diamides containing a halogenated phenyl 3-trifluoroethoxypyrazole moiety. The preliminary bioassays disclosed that IIb, IIIb, and IIIf against Mythimna separata showed comparable activity to chloranthraniliprole (LC 50 : 0.16, 0.16, 0.14, and 0.13 mg•L −1 , respectively). More than half of the target compounds displayed good activity against Plutella xylostella, where IIIf was the most active compound, 25 times more active than chloranthraniliprole (LC 50 : 6.0 × 10 −6 versus 1.5 × 10 −4 mg•L −1 ). For Spodoptera f rugiperda, IIIf displayed slightly inferior potency to chlorantraniliprole (LC 50 : 0.47 versus 0.31 mg•L −1 ). For RyR mutants of S. f rugiperda (G4891E, I4734M), compound IIIf could show higher affinity than chlorantraniliprole according to the binding mode and energy in molecular docking experiments. Calcium imaging technique, molecular docking, density functional theory calculations, and electrostatic potential studies validated that the RyR was the target of the most active candidate IIIf, which deserves further development.

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

“…In vitro fungicidal activity of the target compounds 3a – 3y against Alternaria solani , Botrytis cinerea , Cercospora arachidicola , Fusarium graminearum , Physalospora piricola , R. solani , and Sclerotinia sclerotiorum was tested according to our previous reported SOP method at a concentration of 50 μg/mL. , The tested compound (10 mg) was weighed for the preparation of the mother solution of 25000 μg/mL in 400 μL of N , N -dimethylformamide (DMF), and the test concentration of 500 μg/mL working solution was diluted by adding 100 μL of mother solution to 4900 μL of sterile water with 0.1% Tween 80. Finally, 50 μg/mL of potato glucose agar (PDA) was prepared by the 4 mL working solution mixing with 36 mL of PDA.…”

“…The PK enzyme activity experiment of 3a , 3b , and 3c was detected by a test kit as description in our previous reports. , R. solani was cultured in the potato dextrose broth (PDB) medium for 48–72 h at 25 °C and a rotation speed of 200 rpm; then crude protein was extracted and concentrated according to the operation of kit instructions (G0811W, Suzhou Grace). The protein concentration and compound ( 3a , 3b , 3c , or YZK-C22 ) were set as 200 and 20 μg/mL, respectively.…”

“…The PK enzyme activity was measured according to the instructions with 0.5 h incubation time with the selected compounds. Percent enzymatic inhibition was calculated according to the previously reported method …”

“…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 . A successful example via the PFVS strategy is the discovery of flubeneteram, a novel fungicide targeting SDH. , CADD is carried out by a combination of bioinformatics and computer technology, which can be structure-based drug design (SBDD) and ligand-based drug design (LBDD). − SBDD considers the mode of binding between a receptor and its ligand by homology modeling and molecular docking to understand their interactions. With obtained knowledge, a chemical library with potentially biological activity can be established, and LBDD is used to set up a quantitative structure–activity relationship (QSAR) model by analyzing the structure–activity relationships and then designing new compounds.…”

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. − …”