Strategic Design, Quantitative Structure Activity Relationship And Selective Synthesis Of Some Pyrazoline Derivatives

ABSTRACT

Numerous pyrazoline derivatives have been found to possess considerable biological activities; this fact had led us to model and design 120 trisubstituted 2-pyrazoline derivatives by linking pyrazoline ring system with different substituents in position 1, 3 and 5. Quantitative structure–activity relationship (QSAR) studies were carried out in order to get models that can be used to predict the anti-cancer activity of designed compounds. Data set of compounds consisting of pyrazoline derivatives were collected and their anti-cancer activity were correlated with their physicochemical descriptors using multiple linear regression method. QSAR study revealed three good predictive and statistically significant descriptor models (r2 = 0.7603; r= 0.8720 for training set, Q2 = 0.5348 for cross validation and r 2 = 0.8593; r= 0.9270 for test set); all other statistical parameters were found in the acceptable range (RMSE= 0.33535, s= 0.56, F= 34.05 and P= 0.133). Obtained model showed that the biological activity was proportionally correlated with density and inversely correlated with log P(o/w) partition coefficient and ionization potential. This model was used to predict the biological activity of designed 120 pyrazoline derivatives, and the results were compared with Combretastin A-4. Drug ability of designed compounds was evaluated using Lipinski’s “rule of five” to select compounds for synthesis. Therefor, 33 out of 120 compounds were selected for synthesis. Although only eight of them were found to have less anti-cancer activity (2.64 - 6.45 M) than that of the standard Combretastin A-4 (6.51 M), all the others had much more anti-cancer activity (6.72-14.88 M). These promising results have lured similar investigation of anti-cancer activity of breast cancer of another group of α,β-unsaturated carbonyl derivatives.