Eco-friendly synthesis of novel pyrazole derivatives and their anticancer and CDK2 inhibitory activities

Abstract

A series of 1-(2-pyridinyl)-4-aryl-1H-pyrazole-3,5-diamine derivatives (2–12) were designed and synthesized using a one-pot multicomponent reaction via both microwave-assisted and conventional techniques. The structural properties of the new compounds were established using spectroscopic data. The new derivatives were biologically assessed as promising CDK2 enzyme inhibitors. Then, the target pyrazoles were screened against both HepG2 and MCF-7 malignant cell lines. Compounds 4, 7, and 10 revealed significant CDK2 inhibitory activities with comparable potencies (IC₅₀ = 0.75, 0.77 and 0.85 µM, respectively) to that of roscovitine (IC₅₀ = 0.99 µM). Additionally, compounds 5, 6, and 11 demonstrated the best inhibitory activities, which are twice the activity of roscovitine towards CDK2, with IC₅₀ values of 0.56, 0.46, and 0.45 µM, respectively. Concerning the cytotoxic activity, compound 5 displayed potent cytotoxicity (IC₅₀ = 13.14 and 8.03 µM) against the HepG2 and MCF-7 cell lines, respectively. Further investigation on the mechanism demonstrated that 5 induced apoptosis, increased the proapoptotic protein Bax level, and reduced the antiapoptotic Bcl-2 level in the cells of MCF-7. Finally, the molecular docking study showed bioactive analogues that fit well in the CDK2 active site via various interactions.