Novel pyrrole-sulfonamide derivatives as EGFR inhibitors and radiosensitizers in lung cancer.

Molecular hybridization strategy is of significant importance in drug discovery. This study describes the design and synthesis of sulfonamide and pyrrole hybrid in a single design as a potential epidermal growth factor enzyme (EGFR) inhibitors against non-small lung cancer cell lines (NSCLC). All the synthesized compounds (3-11) were assessed for their in vitro cytotoxic activities against A-549 cell line and evaluated for the ability to inhibit EGFR enzyme. Compound 6 revealed the most potent cytotoxic activity (IC50 = 4.55 μM) compared to doxorubicin (IC50 = 7.52 μM) on A-549 cell line. Similarly, compound 6 exhibited a promising EGFR inhibitory activity with the lowest IC50 (0.065 μM) compared to erlotinib (IC50 0.061 μM). Compound 6 was selected to evaluate its apoptotic effect and the results showed the ability to induce early apoptosis by 1.65 folds better than erlotinib as well as an increase in Bax/Bcl-2 ratio to 1.52 in A-549 cells. Furthermore, the effect of compound 6 on caspase-3 was assessed and the result showed an increase in its level to 14.65 ng/mL. The synergistic effect of gamma radiation (8 Gy) was evaluated for compound 6. The effect of compound 6 was tested against EGFR L858R and EGFR T790M as well as on normal fibroblast lung (WI-38) cell line. Finally, docking study was performed within the active site of EGFR to get more insight on the binding mode of compound 6.