Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway

[Image: see text] A series of novel pyrazolinone chalcones 3–9 have been synthesized through the condensation of azo pyrazolinone derivatives with various aromatic aldehydes. Spectroscopic techniques and elemental analysis have both corroborated this. Furthermore, all compounds were screened in silico for their ability to inhibit cancer proliferation and metastasis by targeting the PI3K/Akt signaling pathway. This inhibitory pathway might be an efficient approach for the death of cancer cells, angiogenesis, and metastasis prevention. Our results indicated that only compound 6b was the top-ranked. It demonstrated the highest binding energies of −11.1 and −10.7 kcal/mol against the target proteins PI3K and Akt, respectively; thus, it was chosen for in vitro studies. Compound 6b exhibited the most effective cytotoxic impact against the Caco cell line with IC(50) of 23.34 ± 0.14 μM. Furthermore, it showed significant inhibition of PI3K/Akt proteins and oxidative stress, leading to elevated Bax and p53 expression, reduced Bcl(–2) expression, and triggered cell cycle arrest at the sub-G0/G1 phase. Additionally, it showed significant downregulation of the Raf-1 gene, leading to ERK1/2 protein inhibition. These findings demonstrate that compound 6b obeyed Lipinski’s rule of five and might be used as a favored scaffold for cancer treatment by inhibiting proliferation and metastasis via inhibition of the PI3K/Akt and Raf-1/ERK1/2 signaling pathways.