Synthesis and Evaluation of Some New 4-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations.

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives and inhibited all the tested Gram-positive isolates, except for (ATCC 14579), with lower IC values (µM) than ampicillin. In addition, and demonstrated the strongest DPPH scavenging and reducing potencies, with being more efficient than BHT. In cell viability assays, and suppressed the proliferation of HCT-116 cells, with the lowest IC values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of and , inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, and were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds , , and were predicted to comply with Lipinski's rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.