RESUMEN
Based on our previous research, a 3D-QSAR model (q2=0.51, ONC=5, r2=0.982, F=271.887, SEE=0.052) was established to predict the inhibitory effects of triazole Schiff base compounds on Fusarium graminearum, and its predictive ability was also confirmed through the statistical parameters. According to the results of the model design, 30 compounds with superior bioactivity compared to the template molecule 4 were obtained. Seven of these compounds (DES2-6, DES9-10) with improved biological activity and readily available raw materials were successfully synthesized. Their structures were confirmed through HRMS, NMR, and single crystal X-ray diffraction analysis (DES-5). The bioactivity of the final products was investigated through an inâ vitro antifungal assay. There was little difference in the EC50 values between the experimental and predicted values of the model, demonstrating the reliability of the model. Especially, DES-3 (EC50=9.915â mg/L) and DES-5 (EC50=9.384â mg/L) exhibited better inhibitory effects on Fusarium graminearum compared to the standard drug (SD) triadimenol (EC50=10.820â mg/L). These compounds could serve as potential new fungicides for future research. The interaction between the final products and isocitrate lyase (ICL) was investigated through molecular docking. Compounds with R groups that have a higher electron-donating capacity were found to be biologically active.
Asunto(s)
Antifúngicos , Fusarium , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad Cuantitativa , Bases de Schiff , Triazoles , Bases de Schiff/química , Bases de Schiff/farmacología , Bases de Schiff/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Fusarium/efectos de los fármacos , Estructura Molecular , Simulación del Acoplamiento MolecularRESUMEN
Fourteen novel Schiff base compounds (AS-1â¼AS-14) containing 5-amino-1H-1,2,4-triazole-3-carboxylic acid and substituted benzaldehyde were successfully synthesized, and their structures were verified by melting point, elemental analysis (EA) and spectroscopic techniques (Fourier Transform Infra-Red (FT-IR) and Nuclear Magnetic Resonance (NMR)). In vitro hyphal measurements were used to investigate the antifungal activities of the synthesised compounds against Wheat gibberellic, Maize rough dwarf and Glomerella cingulate. The preliminary studies indicated that all compounds had good inhibitory effect on Wheat gibberellic and Maize rough dwarf, among which the compounds of AS-1 (7.44â mg/L, 7.27â mg/L), AS-4 (6.80â mg/L, 9.57â mg/L) and AS-14 (5.33â mg/L, 6.53â mg/L) showed better antifungal activity than that of the standard drug fluconazole (7.66â mg/L, 6.72â mg/L); while inhibitory effect against Glomerella cingulate was poor, only AS-14 (5.67â mg/L) was superior to that of fluconazole (6.27â mg/L). The research of structure-activity relationship exhibited that the introduction of halogen elements on the benzene ring and electron withdrawing groups at the 2,4,5 positions on the benzene ring was beneficial to the improvement of the activity against Wheat gibberellic, while the large steric hindrance was not conducive to the improvement of the activity. Additionally, except for AS-1, AS-3 and AS-10, the other compounds had one or several ratio systems to achieve synergistic effect after recombination with pyrimethamine, among which AS-7 had significant synergistic effect and was expected to be a combinated agent with application prospects. Finally, the molecular docking results of isocitrate lyase with Wheat gibberellic displayed that the presence of hydrogen bonds enabled stable binding of compounds to receptor proteins, and the residues of ARG A: 252, ASN A: 432, CYS A: 215, SER A: 436 and SER A: 434 were the key residues for their binding. Comparing the docking binding energy and biological activity results, it was revealed that the lower the docking binding energy was, the stronger the inhibitory ability of the Wheat gibberellic, when the same position on the benzene ring was substituted.