Three-dimensional quantitative structure activity relationship (QSAR) of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA) revisited study

Abstract

In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS) analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity.

Background: Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described for evaluation of antioxidant properties.

Results: Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC) human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR) study was initiated.

Conclusions: Chalcones heating provides a rapid and expedient route to a series of pyrazoles to investigate their chracterization scavenging properties. Given their favorable properties, in comparison with known anticancer, these pyrazole derivatives are promising leads for further development and optimization.

Scheme 1

One-step synthesis of chalcones and their use in the synthesis of 3, 5-diaryl-1-substituted-4,5-dihydropyrazoles.

Figure 1

Superimposition of compound D5 with the best pharmacophore model.

Figure 2

Correlation line of log actual activity vs log estimated activity (r 0.695) of the best pharmacophore model.

Figure 3

Alignment of compounds D1-30 with the best 3D QSAR pharmacophore.

Figure 4

Correlation line of COMFA_PIC50 vs PIC50 of the pharmacophore model.

Figure 5

Correlation line of PIC50 vs COMFA_PIC50 of the pharmacophore model.

Figure 6

(a). Electrostatic contour plot: positive (contribution level of 70%) and negative (contribution level of 30%) charge favoring areas are represented as blue and red contours, respectively (b). Steric contour plot: favored (contribution level 70%) and unflavored (contribution level 30%) areas are represented as green and yellow contours, respectively.