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CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4- d ]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4- d ]pyrimidinone derivatives bearing N 5 -2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC 50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.

Newly designed thiazolidine-2,4-diones 3 - 7a - c were synthesized, and their anticancer activities were screened against three cancer lines. They showed potent activities against HepG2 compared to the other HCT116 and MCF-7 tumor cell lines. Compounds 7c and 6c were detected as highly effective derivatives against MCF-7 (IC 50 = 7.78 and 8.15 µM), HCT116 (IC 50 = 5.77 and 7.11 µM) and HepG2 (IC 50 = 8.82 and 8.99 µM). The highly effective derivatives 6a - c and 7a - c were tested against VERO normal cell lines. All derivatives were evaluated for their VEGFR-2 inhibitory actions and demonstrated high to low activities, with IC 50 values varying from 0.08 to 0.93 µM. Moreover, derivatives 5a - c , 6a - c and 7a - c were assessed to verify their in vitro binding affinities to PPARγ and insulin-secreting activities. Finally, docking studies were performed to explore their affinities and binding modes toward both VEGFR-2 and PPARγ receptors.