Novel Evodiamine-Based Sulfonamide Derivatives as Potent Insecticide Candidates Targeting Insect Ryanodine Receptors.

Pests represent an important impediment to efficient agricultural production and pose a threat to global food security. On the basis of our prior research focused on identifying insecticidal leads targeting insect ryanodine receptors (RyRs), we aimed to identify evodiamine scaffold-based novel insecticides. Thus, a variety of evodiamine-based derivatives were designed, synthesized, and assessed for their insecticidal activity against the larvae of Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). The preliminary bioassay results revealed that more than half of the target compounds exhibited superior activity compared to evodiamine, matrine, and rotenone against M. separata. Among these, compound 21m displayed the most potent larvicidal efficiency, with a remarkable mortality rate of 93.3% at 2.5 mg/L, a substantial improvement over evodiamine (10.0% at 10 mg/L), matrine (10.0% at 200 mg/L), and rotenone (30.0% at 200 mg/L). In the case of P. xylostella, compounds 21m and 21o displayed heightened larvicidal activity, boasting LC50 values of 9.37 × 10-2 and 0.13 mg/L, respectively, surpassing that of evodiamine (13.41 mg/L), matrine (291.78 mg/L), and rotenone (18.39 mg/L). A structure-activity relationship analysis unveiled that evodiamine-based derivatives featuring a cyclopropyl sulfonyl group at the nitrogen atom of the B ring and a fluorine atom in the E ring exhibited more potent larvicidal effects. This finding was substantiated by calcium imaging experiments and molecular docking, which suggested that 21m could target insect RyRs, including resistant mutant RyRs of P. xylostella (G4946E and I4790M), with higher affinity than chlorantraniliprole (CHL). Additionally, cytotoxicity assays highlighted that the potent compounds 21i, 21m, and 21o displayed favorable selectivity and low toxicity toward nontarget organisms. Consequently, compound 21m emerges as a promising candidate for further development as an insecticide targeting insect RyRs.

Bioactivity-Guided Synthesis Accelerates the Discovery of Evodiamine Derivatives as Potent Insecticide Candidates.

Pests threaten worldwide food security by decreasing crop yields and damaging their quality. Natural product-based molecular design and structural optimization have been one of the most effective ways to innovate pesticides for integrated insect management. To continue our previous studies on the discovery of insecticidal lead, a series of evodiamine derivatives were designed, synthesized, and evaluated for their insecticidal activities. The bioassay results demonstrated that compounds Ian and Iao exhibited 90 and 80% insecticidal activities against Mythimna separata at 2.5 mg/L, respectively, which were superior to evodiamine (10% at 10 mg/L), matrine (45% at 600 mg/L), and rotenone (30% at 200 mg/L). Compounds Ian-Iap showed 90% insecticidal activities against Plutella xylostella at 1.0 mg/L, far more potent than those of evodiamine, matrine, and rotenone. Compound Ian displayed 60% insecticidal activity against Helicoverpa armigera at 5.0 mg/L, while evodiamine, matrine, and rotenone showed very poor activities. The study on the insecticidal mechanism of action by a calcium imaging experiment indicated that the insect ryanodine receptors (RyRs) could be the potential target of Ian. Furthermore, the molecular docking indicated that Ian anchored in the binding site of the RyR of P. xylostella. The above results manifested the potential of evodiamine derivatives as potent insecticide candidates.

Discovery of evodiamine derivatives as potent insecticide candidates.

In the search for novel more effective insecticides, natural products could be used as ideal template compounds due to their good environmental compatibility, various bioactivities, unique scaffolds and mode of action. We have found that natural product evodiamine, the main active component from the fruits of Evodia rutaecarpa (Juss.) Benth, displayed obvious insecticidal activities against lepidoptera pests. To continue our research, a series of evodiamine derivatives 3a-3aa were rationally designed and synthesized. The larvicidal activities results indicated that most of target compounds displayed better efficacy than evodiamine, matrine, and rotenone against Mythimna separata, Plutella xylostella and Helicoverpa armigera, among which 3z exhibited excellent larvicidal activities (65% at 2.5 mg/L against M. separata, 75% at 1.0 mg/L against P. xylostella, and 85% 10 mg/L against H. armigera, respectively), much better than evodiamine (0%), matrine (0%), and rotenone (0%). The preliminary structure activity relationships demonstrated that the fluorine atom at the E ring of evodiamine had a positive influence on the larvicidal activity. The calcium imaging experiment studies indicated that 3z could act on the ryanodine receptor (RyR) of M. separata and was an effective calcium activator for RyR.

A faster detection method for high-sensitivity cardiac troponin-POCT quantum dot fluorescence immunoassay.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) is a significant biomarker of myocardial injury and necrosis, and has momentous clinical significance for the diagnosis and risk stratification of acute myocardial infarction (AMI). The purpose of this study is to determine the accuracy and sensitivity of hs-cTn detection in whole blood samples with a new faster method-Point of Care Testing (POCT) quantum dot fluorescence immunoassay. METHODS: Blood samples from 415 patients with chest pain suggestive of AMI from August to November 2017 in The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University were analyzed. We first performed hs-cTnI test with anticoagulated whole blood by POCT quantum dot fluorescence immunoassay. After the sample was centrifuged, the plasma sample was taken for detection of hs-cTnT by electrochemiluminescence immunoassay. The final diagnosis was determined by two independent cardiologists. RESULTS: Firstly, by measuring the receiver operating characteristic curve (ROC curve) and the area under the curve (AUC) of 32 patients with AMI, it was found that the measurement accuracy of the POCT quantum dot fluorescence immunoassay was relative high (AUC was 0.866, 95% confidence interval is 0.783 to 0.949). There was no statistical difference between POCT quantum dot fluorescence immunoassay and electrochemiluminescence troponin assay [Z value =1.527, P value =(0.063, 0.064)]. In addition, the study also calculated the performance evaluation index of POCT quantum dot fluorescence immunoassay (critical value 0.04 ng/mL) and analyzed the ROC curve to compare the diagnostic accuracy of both for cardiogenic diseases and the diagnostic efficacy of patients with AMI. Our study found that the new method-POCT quantum dot fluorescence immunoassay had high diagnostic efficiency, which was similar to the traditional electrochemiluminescence method. CONCLUSIONS: The measurements of hs-cTn by the method of Vazyme POCT quantum dot immunofluorescence and Roche electrochemiluminescence method have a good correlation (Y=37.419+131.009X, r=0.935), and also have a good consistency in the diagnosis of AMI. In addition, compared with the traditional electrochemiluminescence method, quantum dot immunofluorescence is faster and more suitable for clinical needs.