A series of diphenyl ether-containing pyrazole-carboxamide derivatives was designed and synthesized as new succinate ubiquinone oxidoreductase (SQR) inhibitors. This highly potent molecular scaffold was developed from a moderately activie hit 3, obtained from our previous pharmacophore-linked fragment virtual screening (PFVS) method. The results of greenhouse tests indicated that some analogues showed good SQR inhibitory activity, with promising fungicidal activity against Rhizoctonia solani and Sphaerotheca fuliginea at a dosage of 200 mg/L. Most surprisingly, compound 62 showed the highest SQR inhibitory activity with a Ki value of 0.081 μM, about 4-fold more potent than penthiopyrad (Ki = 0.307 μM). In addition, compounds 43 and 62 displayed excellent fungicidal activity even at a dosage as low as 6.25 mg/L, which was superior to thifluzamide. Moreover, compound 62 exhibited excellent protection effect against R. solani and provided about 81.2% protective control efficancy after 21 days with two sprayings. The present work indicated that these two compounds could be used as potential agricultural fungicides targeting SQR.Keywords: complex II; diphenyl ether; molecular docking; structure−activity relationship; succinate ubiquinone oxidoreductase;

Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a Ki value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R2 group had a significant effect on binding with the protein.

•A series of N-(2-benzooxazol-5-yl)-pyrazole-4-carboxamides were designed and synthesized.•All compounds showed excellent inhibitory activity against porcine SCR.•Compound 13b with a Ki value of 11 nM was identified as the most potent candidate.•13b is non-competitive inhibitor with respect to the substrate cytochrome c and DCIP.•The binding model of the title compounds was established by computational simulations.Succinate–ubiquinone oxidoreductase (SQR, EC 1.3.5.1, complex II), an essential component of cellular respiratory chain and tricarboxylic acid (or Krebs) cycle, has been identified as one of the most significant targets for pharmaceutical and agrochemical. Herein, with the aim of discovery of new antibacterial lead structure, a series of N-benzoxazol-5-yl-pyrazole-4-carboxamides were designed, synthesized, and evaluated for their SQR inhibitory effects. Very promisingly, one candidate (Ki = 11 nM, porcine SQR) was successfully identified as the most potent synthetic SQR inhibitor so far. The further inhibitory kinetics studies revealed that the candidate is non-competitive with respect to the substrate cytochrome c and DCIP. Computational simulations revealed that the titled compounds have formed hydrogen bond with D_Y91 and B_W173 and the pyrazole ring formed cation-π interaction with C_R46. In addition, in R1 position, –CHF2 group has increased the binding affinity and decreased the entropy contribution, while –CF3 group displayed completely opposite effect when bound with SQR. The results of the present work showed that N-benzoxazol-5-yl-pyrazole-4-carboxamide is a new scaffold for discovery of SQR inhibitors and worth further study.A series of N-benzooxazol-5-yl-pyrazole-4-carboxamides were designed and synthesized as potent SQR inhibitors. One candidate (Ki = 11 nM) was successfully identified as the most potent synthetic SQR inhibitor so far.

•A sensitive, simple, and label-free capacitive sensor developed for the detection of OPs.•As-prepared sensor fabricated by alternate assembly of exfoliated LDH nanosheets and carboxymethyl-β-cyclodextrin.•Such a newly designed (LDH/CMCD)n multilayer film, combining the individual properties of CMCD and LDH nanosheets.•The first smart combination of LDH/CMCD LBL film and capacitive transduction.Novel organic–inorganic hybrid ultrathin films were fabricated by alternate assembly of cationic exfoliated Mg–Al-layered double hydroxide (LDH) nanosheets and carboxymethyl-β-cyclodextrin (CMCD) as a polyanion onto a glassy carbon electrode (GCE) via a layer-by-layer (LBL) approach. The multilayer films were then characterized by means of X-ray powder diffraction (XRD), infrared spectroscopy (IR), and scanning electron microscopy (SEM). These films were found to possess a long range stacking order in the normal direction of the substrate with a continuous and uniform morphology. Its electrochemical performance was systematically investigated. Our results demonstrate that such a newly designed (LDH/CMCD)n multilayer film, combining the individual properties of CMCD (a high supramolecule recognition and enrichment capability) together with LDH nanosheets (a rigid inorganic matrix), can be applied to a sensitive, simple, and label-free capacitive detection of acephatemet (AM). Molecular docking calculations further disclose that the selective sensing behavior toward AM may be attributed to the specific binding ability of CMCD to AM. Under the optimized conditions, the capacitive change of AM was proportional to its concentration ranging from 0.001 to 0.10 μg mL−1 and 0.1 to 0.8 μg mL−1 with a detection limit 0.6 ng mL−1 (S/N=3). Toward the goal for practical applications, this simple probe was further evaluated by monitoring AM in real samples.