In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1 -indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]- -(thiazol/benzothiazol-2-yl)acetamides ( ) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds - on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1 -Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]- -(6-ethoxybenzothiazol-2-yl)acetamide ( ) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC values of 6.43 ± 0.72 μM, 9.62 ± 1.14 μM, and 8.07 ± 1.36 μM, respectively, when compared with erlotinib (IC = 17.86 ± 3.22 μM, 19.41 ± 2.38 μM, and 23.81 ± 4.17 μM, respectively). Further mechanistic assays demonstrated that compound enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC value of 2.80 ± 0.52 μM when compared with erlotinib (IC = 0.04 ± 0.01 μM). However, compound did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound is a promising EGFR inhibitor that warrants further clinical investigations.