Synthesis And Antibacterial Activity Of Quinazoline-2,4-dione Derivatives Containing 1,2,4-triazole Heterocycles

Quinazoline-2,4-dione, known as a kind of nitrogen-containing heterocyclic derivatives, have been widely used in the fields of pesticide and medicine because of their broad spectrum of biological properties such as antibacterial and antifungal, insecticidal and herbicidal activities.Meanwhile, 1,2,4-triazole Schiff-base(or aryl hydrazone) derivatives also display broad spectrum of biological activities as a result of not only containing nitrogen-containing 1,2,4-triazole heterocycle but also-C=N unit. In this paper, a series of novel quinazoline-2,4-dione derivatives containing 1,2,4-triazole with-C=N or-(C=O)-NHN=C- fragments were designed and synthesized by the introduction of n-butyl linker in the 1-position of quinazoline-2,4-dione based on the principle of combination of active groups. All of my work and findings are summarized below:1. Eighteen novel quinazoline-2,4-dione derivatives containing 1,2,4-triazole Schiff-base units were designed and synthesized from the raw material methyl 2-aminobenzoate by the formation of urea, cycle-closing, N-alkylation and the Schiff-base reaction and their structures were characterized by 1H NMR, 13 C NMR, MS, IR and elemental analysis, and evaluated subsequently for antibacterial activities in vitro against Xanthomonas oryzae pv.oryzae(Xoo), Xanthomonas axonopodis pv. citri(Xac) and Ralstonia solanacearum at the concentration of 200 and 100 ?g/m L by the turbidimeter test using the commercial bactericides Thiodiazole copper and Bismerthiazol as the positive control. The preliminary antibacterial test indicated that all the target compounds possessed an excellent inhibition activity(? 93.4%) against Xoo at the concentration of 200 ?g/m L which was obviously better than those of control agents Thiodiazole copper(50.1%) and Bismerthiazol(72.8%). Notably,compounds 7a, 7c–7g and 7j–7l still displayed 100% inhibition rates against Xoo even at the concentration of 100 ?g/m L. The EC50 values were obtained based on the preliminary test data of compounds 7a, 7c–7g and 7j–7l against Xoo and compounds 7g and 7l proved the two most active molecules with the minimum EC50 of 35.58 and 30.59 ?g/m L, respectively,which were far below compared with the reference drug Bismerthiazol(92.61 ?g/m L).2. Seventeen novel quinazoline-2,4-dione derivatives containing 1,2,4-triazole aryl hydrazone units were designed and synthesized from the raw material methyl 2-aminobenzoate by the formation of urea, cycle-closing, N-alkylation, hydrazinolysis and condensation and their structures were characterized by 1H NMR, 13 C NMR, MS, IR and elemental analysis, and evaluated subsequently for antifungal activities in vitro against G. zeae, V. dahlia, P.infestans, B. cinerea, P. sasakii and C. mandshurica by the mycelial growth rate method using Hymexazol as the positive control. The results showed that all of the target compounds didn't show significant inhibitory activities against the above six plant pathogenic fungi compared with Hymexazol at the concentration of 50 ?g/m L. Next, the above 17 compounds were evaluated for antibacterial activities in vitro against Xanthomonas oryzae pv. oryzae(Xoo), Xanthomonas axonopodis pv. citri(Xac) and Ralstonia solanacearum at the concentration of 200 and 100 ?g/m L, respectively. The preliminary antibacterial test indicated that the antibacterial activities of compounds 7a', 7d', 7f' and 7h' against Xoo at100 ?g/m L were 81.1, 60.3, 87.6 and 58.9%, respectively, exceeding that of Thiodiazole copper(46.9%). Most importantly, the inhibitory activities of compounds 7b'–7c', 7e'–7i'and 7o' against Xac at 100 ?g/m L were 71.2, 78.2, 73.1, 63.3, 61.7, 61.2, 84.4 and 51.3%,respectively, which were much higher than that of Thiodiazole copper(32.6%). Moreover,compounds 7h' displayed 95.5% and 66.5% inhibitory rates against Ralstonia solanacearum at the concentration of 200 and 100 ?g/m L, respectively, which were also better than that of Thiodiazole copper(53.9% and 32.3%, respectively). The further EC50 test demonstrated that compounds 7b'–7c', 7e'–7i' and 7o' exhibited excellent inhibitory activities in vitro against Xac with EC50 values of 44.67, 44.59, 53.83, 62.84, 59.87, 71.05, 42.85 and 89.05 ?g/m L,respectively.3. The three-dimensional quantitative structure-activity relationship(3D-QSAR) model of quinazoline-2,4-dione derivatives 7a'–7q' was studied using the comparative molecular field analysis(Co MFA) based on the EC50 values against Xac. Thirteen molecules of the whole compounds were chosen as the training set for Co MFA model and the other four compounds were used as the testing set. The results demonstrated that the Co MFA model exhibited good predictive capability with r2 and q2 values of 0.998 and 0.579, respectively.