Novel 2-Sulfanylquinazolin-4(3H)-one Derivatives as Multi-Kinase Inhibitors and Apoptosis Inducers: A Synthesis, Biological Evaluation, and Molecular Docking Study

The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, 5d, showed broad-spectrum anti-cancer activities against all tested cell lines (IC50 = 1.94-7.1 & mu;M) in comparison to doxorubicin (IC50 = 3.18-5.57 & mu;M). Interestingly, compound 5d exhibited lower toxicity in the normal WI-38 cells (IC50 = 40.85 & mu;M) than doxorubicin (IC50 = 6.72 & mu;M), indicating a good safety profile. Additionally, the potential of compound 5d as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound 5d exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound 5d was the least active against CDK2 (2.097 & PLUSMN; 0.126 & mu;M) when compared to the positive control roscovitine (0.32 & PLUSMN; 0.019 & mu;M). The apoptotic activity investigation in HepG2 cells demonstrated that compound 5d arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound 5d showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors.

Automated summary

The discovery of multi-targeted kinase inhibitors has potential therapeutic implications for multi-genic diseases, such as cancer. This study focuses on the design and synthesis of new quinazolin-4-one derivatives as anti-cancer agents. The most active compound, 5d, exhibits broad-spectrum anti-cancer activities and lower toxicity in normal cells compared to the standard drug doxorubicin.