New Pyrazole-Based Compounds as Potential Multi-Kinase Inhibitors with Antiproliferative Activity: Synthesis, In Vitro Biological Evaluation, and In Silico Studies

New pyrazole-based compounds were synthesized via a one-pot three-component reaction including 5-methyl-2,4-dihydro-3H-pyrazol-3-one, 2,6-dichlorobenzaldehyde, and various active methylene compounds. The chemical structures of these compounds were fully elucidated using various elemental and spectral analyses. The synthesized compounds were evaluated for their antiproliferative activity against HepG2 (liver), MCF-7 (breast), and HCT-116 (colon) human cancer cell lines, alongside normal WI-38 fibroblasts. Several derivatives displayed moderate-to-good cytotoxic activity with varying degrees of selectivity. In particular, compound 6 exhibited the highest potency (HepG2 IC50 = 6.17 µM; MCF-7 IC50 = 8.65 µM), with selectivity (SI = 4.1) higher than that of doxorubicin (SI = 1.4). In silico ADME studies predicted favorable drug-like properties and good oral bioavailability for all compounds, with limited blood–brain barrier penetration. Molecular docking against KIT, CDK2, and c-Met kinases revealed consistent multi-kinase binding for the most active derivatives, correlating well with their in vitro antiproliferative effects. Density functional theory calculations further supported these findings by elucidating electronic features relevant to molecular reactivity and ligand–protein interactions. Overall, this study identifies a promising pyranopyrazole-based scaffold for further optimization toward selective multi-kinase anticancer agents.