Development of Benzothiazole-grafted Pyrazolo[1,5-a]pyrimidines as new CDK2 inhibitors and anti-prostate cancer agents.

In the current medical era, CDK2 kinase has emerged as a promising target in the global fight against cancer. Recent research reported the overexpression of CDK2 in prostate cancer cells, which highlighted the potential of CDK2 inhibition as a practical therapeutic approach for this disease that stands out as a challenging global health issue. On account of their interesting biological activities, especially anti-cancer properties, the two privileged scaffolds benzothiazole and pyrazolo[1,5-a]pyrimidine were utilized in this study to develop three series of 16 novel small molecules (8a-k, 12a-c, and 14a-b) as potential anti-prostate cancer agents targeting CDK2. The synthesized derivatives were assessed for cytotoxic effects against two prostate cancer cell lines, DU-145 and PC-3. Compounds 8f, 12c, and 14b exhibited the highest anti-cancer activity. Further investigation showed that these molecules inhibit critical cell cycle regulators by arresting DU-145 cells at the G0/G1 phase. Apoptosis induction was verified using Annexin V-FITC/Propidium iodide (PI) assays, which indicated a noteworthy apoptosis level in DU-145 cells. The compounds were validated as CDK2 inhibitors via in-vitro assays, with 8f demonstrating the highest potency, exceeding that of the reference drug Roscovitine. Molecular docking studies revealed substantial binding affinities of compounds 8f, 12c, and 14b to the ATP-binding site of CDK2, supported by essential hydrogen bonding and hydrophobic interactions. Overall, these study's findings indicate the potential of these benzothiazole-grafted pyrazolo[1,5-a]pyrimidines as effective therapeutic agents for prostate cancer.