No abstract

Twenty novel phthalazinone‐based compounds were designed as acetylcholinesterase (hAChE) inhibitors. Compounds 7e and 17c demonstrated comparable or superior activity compared to donepezil, respectively, in in vitro enzyme assay. Moreover, both compounds 7e and 17c possess minimal toxicity on hepatic and neuroblastoma cell lines. Besides, it was proved that compounds 7e and 17c have percentage alternations and a transfer latency time comparable to donepezil and can alleviate the cognitive impairment caused by the scopolamine‐induced model in mice. The kinetic analysis for compound 17c suggested this compound as a mixed‐type inhibitor that could bind to both the peripheral (PAS) and the catalytic site (CAS) of the hAChE enzyme. The synthesized molecules were subjected to in silico analyses, including molecular docking studies, and the outcomes were consistent with the in vitro findings.

The novel series of furan‐bearing pyrazolo[3,4‐b]pyridines were designed as cyclin‐dependent kinase 2 (CDK2) inhibitors and as p53–murine double minute 2 (MDM2) inhibitors. The newly synthesized compounds were screened for their antiproliferative activity toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines. The most active compounds on both cell lines were additionally evaluated for their in vitro CDK2 inhibitory activity. Compounds 7b and 12f displayed enhanced activity (half‐maximal inhibitory concentration [IC50] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC50 = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively. Moreover, the most active spiro‐oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53–MDM2 interaction in vitro (IC50 = 3.09 ± 0.12 µM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the negative control. Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro‐oxindole 16a with p53–MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

Finally, these compounds were also found to be dual inhibitors of VEGFR-2 and EGFR in the in vitro enzyme assay with higher potency against the former (IC50 = 0.023-0.41 nM).