DFT and QSAR investigations of substituent effects in pyrazolooxazine derivatives: Activity prediction

The theoretical investigation of the physico-chemical properties of pyrazolooxazine derivatives, which could exhibit anti-inflammatory activity, has been carried out using DFT computations at the B3LYP/6-311++G (d, p) level. It appears that both pyrazolooxazin-2-one (1) and pyrazolooxazin-2-thione (2) exhibit thermal stability whereas the electron donating character of the latter is higher than that of the former species. Molecular electrostatic potential surfaces (MESP) have been used in order to determine the activity sites of these species. The HSAB (Hard and Soft Acids and Bases) principle helped to determine the reactivity as well as the effect of substituting groups on the molecules. The stability of these compounds has been analyzed using natural bond orbital analyses NBO. Then, the structure-activity properties of a large series of derivatives were investigated using the HyperChem 8.0.6 software considering the Lipinski's "rule of five". The results of QSAR analyses showed that the most promising compound among others, named f(1) (a thiophen ring being attached to the nitrogen atom 3 of 1) should be a good candidate for experimental testing.