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 r2= 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. IV New data set consist of α,β-unsaturated carbonyl derivatives were collected. Their anti-cancer activity and descriptors were correlated using multiple linear regression method. The best descriptor model was selected yielding a very high performance in terms of coefficient of determination (r2) as 0.84684 for training set and 0.9430 for test set; other statistical parameters calculated to justify the statistical quality of model were in acceptable range, RMSE= 0.14550, s= 0.384, F= 101.43 and P= 0.010. Model equation showed that there is proportional correlation between the biological activity, density and log P(o/w) partition coefficient, and inverse correlation with potential energy. Derived model was used to predict the activity of designed α-β unsaturated carbonyl derivatives against human breast cancer. All compounds gave biological activity ranging from 3.74 to 6.24 M less than that given by standard drug Tamoxifen (7.39 M). The drug ability of these compounds were also evaluated through Lipinski’s parameters, and they conformed with them. In synthetic work, different aromatic acetophenone derivatives were treated with some substituted aromatic benzaldehydes in the presence of ethanol as solvent and sodium hydroxide as basic medium to give substituted α,β-unsaturated carbonyl derivatives. These derivatives were further converted into pyrazolines by condensation of various synthesized α,β-unsaturated carbonyl derivatives with hydrazine hydrate. The structures of previous compounds were characterized by melting point, FT-IR and other physicochemical properties. New Chloroacetyl pyrazoline derivatives have been synthesised by the condensation of pyrazoline derivatives obtained from previous step with chloroacetyl chloride. These derivatives were tested as alkylating agents in the reaction with sulfanilamide and sulfadoxine in dry DMF and anhydrous K2CO3 with stirring under reflux. Thus the corresponding 1-[(aryl)aminoacetyl] - V 3,5-diaryl-2-pyrazoline derivatives have been obtained. The structures of newly synthesized trisubstituted pyrazoline derivatives were established on the basis of melting point, FT-IR, UV, MS, 1H- NMR spectroscopies analysis and other physicochemical properties. All the synthesized compounds were isolated in satisfactory yields. Docking studies were performed for synthesized compounds in order to evaluate their affinity to cancer proteins. 1JD0 protein obtained from protein data bank was selected for docking study of pyrazoline derivatives and acetazolamide carbonic anhydrase inhibitor was used as the reference drug. The docking scores were calculated, least energy indicated the easy binding character of ligand and receptor. Some compounds have shown excellent docking scores (-21.9174, -22.2056, -22.0545 and -21.2136 kcal/mol respectively) comparing with that standard drug AZA (-21.0578 kcal/mol). 3DKC protein was selected for docking study of α,β-unsaturated carbonyl derivatives. The result suggested that all compounds were capable of forming metal complex interaction and their docking score ranged from -22.9170 to -16.1714 kcal/mol. All in silico studies were achieved by ACD\Lab and MOE soft wares.