Study On Synthesis, Biological Activities And 3D-QSAR Of N-(Di-N-Oxoquinoxaline Carbamoyl)-N’-Alkylureido Derivatives

In order to discover lead compounds exhibiting promising biological activities, we designed new quinoxaline 1,4-di-N-oxides derivatives by applying the classical bioisosterism strategy and taking into consideration the role of the quinoxaline nucleus and urea as important scaffolds.We explored optimal synthetic routes, reaction condition as well as reaction mechanism of intermediates and target products, analyzed the physicochemical and spectroscope properties of the compounds. The structural properties of the compounds were confirmed by nuclear magnetic resonance (1H NMR,13C NMR), infrared.The structure of target compound was as follows.We performed an evaluation of herbicidal and plant growth regulating activity of new quinoxaline 1,4-di-N-oxides derivatives by applying the principle of "Petri dish test for herbicidal bioactivity (NY/T 1155.1-2006)", chose Diuron as contrast drug, monocots (barnyard grass, rice) and dicotyledon (amaranthus, colza) were investigated at the concentrations ranging from 25mg/L to 400mg/L. The preliminary bioassay results indicated that the activity value differed from compounds, test concentration and plants. The derivatives showed growth promotion against monocots (barnyard grass, rice) at lower concentrations, especially, the percentage of growth promotion of 3-methyl-2-{[N-(o-methoxy) phenylcarbamoyl] hydrazino carbonyl} quinoxaline 1,4-dioxide against rice superior to 57%. Accordingly, the compouds were active with moderate growth inhibition at higher concentrations, like some compouds with more than 80% of growth inhibition against Echinochloa Beauvois at 400 mg/L. Compounds demonstrating moderate growth promotion were tested against colza at lower concentrations, while the former expressed more significantly, some compounds showed higher growth inhibition against Amaranthus than Echinochloa Beauvois. Overall, the growth inhibition activity value of Diuron was superior to that of the target compounds.Finally, we resorted to the quantitative structure-activity relationships (QSAR) theory, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to establish 3D-QSAR model on herbicidal activity of 26 target compounds against Amaranthus. We built CoMFA and CoMSIA models capable of estimating the relationship of the activity and molecular structure, the CoMFA model yielded a cross-validated q2 value of 0.502, a non-cross-validated r2 value of 0.917, a standard error of estimate of 0.027, and the contributions of steric and electrostatic fields to bioactivity were 58.7%and 41.3%. The CoMSIA model yielded a cross-validated q2 value of 0.564, a non-cross-validated r2 value of 0.900, a standard error of estimate of 0.030, and the contributions of steric effect, electrostatic effect to bioactivity were 27.5%,72.5%. The relationship between the structure and bioactivity was graphically interpreted in terms of field contour maps, and that can be helpful in the design of promising quinoxaline-di-N-oxide derivatives with potent bioactivity.