Synthesis And Antimicrobial Activities Of Novel Quinazolinone Derivatives Bearing 1,2,4-triazoles

Nitrogen-containing heterocycles play an important role in the pesticides development due to their broad-spectrum biological activities and various activity sites. Quinazolinone, an important class of fused heterocyclic, exhibited wide biological avtivities. Meanwhile, 1,2,4-triazole heterocyclic were widely used in drug design, especially in the antimicrobial aspect. Previous research had shown that one molecule contain different types of biological parts may have better biological activities than just one. Fluquinconazole, as the best-known example of a combination of quinazolinone backbone with 1,2,4-triazole heterocycle, has been extensively used as an agricultural fungicide for crop protection. Moreover, in our previous study a series of quinazoline derivatives containing 1,2,4-triazole Schiff-base unit were synthesized and some compounds were found to exhibit a certain fungicidal activity.On the basis of considerations, we selected quinazolin-4(3H)-one as the lead compound, through a methylene bridge introducing 1,2,4-triazole benzyl sulfide, 1,2,4-triazole Mannich base and 1,2,4-triazole Schiff base, respectively. Design and synthesized A, B and C series of target compounds. The structures of the target compounds were characterized by IR, ~1H NMR and 13 C NMR spectra and elemental analysis. Antimicrobial test showed that some of the title compounds have good antibacterial activities and antifungal activities. All the work was shown as below:1. Three series quinazolinone derivatives containing 1,2,4-triazole benzyl sulfide, 1,2,4-triazole Mannich base and 1,2,4-triazole Schiff base were synthesized. And the crystal structures of compounds A9 and B5 were determined by X-ray single crystal diffraction.2. Discussed the effect of different bases, reaction time and acidified pH on the yield of intermediate V. The result showed the optimized reaction condtion was a 5 % aqueous solution as catalyst, refluxed 6 h, acidified pH to 7.3. The antibacterial activity test in vitro against Xanthomonas oryzae pv. oryzae(Xoo), Xanthomonas axonopodis pv. citri(Xac) and Tobacco bacterial wilt via the the turbidimeter test at the concentration of 200 and 100 ?g/mL, respectively. The results of the bioassays showed that some target compounds exhibited good antibacterial activity. For example, compounds A19, C1, C6, C10, C11, C19 and C22 showed excellent antibacterial activites against Xoo, with the inhibition rates of 100% at the two concentrations, which superior to the positive control bismerthiazol. Compounds A19, C1, C2, C7, C17 and C20 also exhibited excellent activity against Xac with the inhibition rates of 100% at the two concentrations, better than bismerthiazol. Compound A19 showed the best antibacterial activity against Xoo and Xac, with EC50 values of 47.6 and 22.1 ?g/mL, respectively. The series of compounds showed a not obvious activity aginst Tobacco bacterial wilt.4. The antifungal activity test in vitro against G. zeae, P. infestans, C. mandshurica, P. sasakii, F. oxysporum, B. cinerea, S. sclerotiorum, B. cinerea pers., G. fructigenum, C. capsici were tested by the mycelial growth rate method at the concentration of 50 ?g/mL. The results of the bioassays showed that compounds A5, A8 and A11 showed good antifungal activity against P. sasakii with the inhibition rates of 51.3%, 65.9% and 75.4%, respectively. This was superior to or comparable to hymexazol(51.2%). Compounds A8, A12 and A19 with the inhibition rates of 65.1%, 54.9% and 56.2% against C. capsici, better than hymexazol(45.0%). Compounds C1-C25 showed good antifungal activity against S. sclerotiorum, all the compounds inhibition rate more than 50%, compounds C14, C18, C20 and C22 exhibited the best activity.5. In view of compounds C1-C25 antibacterial activity against Xoo. We had done a molecular docking study. The receptor crystal structure of Cas5d(3VZI) was obtained from Protein Data Bank. Docking of small molecules in the receptor binding site, researched the binding energy of the complex and the bingding addinity of binding models. The docking results showed that most compounds having binding energy values below the standard drug bismerthiazol. Compound C22 with the lowest binding energy, showed that it had good bingding addinity with the receptor. And found many ineractions in the complex showed that compound C22 was located in a pocket in the active site.