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

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SEVER B., ALTINTOP M. D., ÖZDEMİR A., AKALIN ÇİFTÇİ G., Ellakwa D. E., Tateishi H., ...More

MOLECULES, vol.25, no.21, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 21
  • Publication Date: 2020
  • Doi Number: 10.3390/molecules25215190
  • Journal Name: MOLECULES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, Agricultural & Environmental Science Database, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, EMBASE, MEDLINE, Metadex, Veterinary Science Database, Directory of Open Access Journals, Civil Engineering Abstracts
  • Keywords: EGFR, COX-2, cancer, indole, oxadiazole, thiazole, benzothiazole, apoptosis, molecular docking, RECEPTOR TYROSINE KINASE, BIOLOGICAL EVALUATION, DERIVATIVES, CANCER, INDOMETHACIN, SCAFFOLD, DESIGN, AGENTS, PARAMETERS, TARGET
  • Anadolu University Affiliated: Yes


Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (2a-i) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds 2a-i on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1H-Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(6-ethoxybenzothiazol-2-yl)acetamide (2e) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC50 values of 6.43 +/- 0.72 mu M, 9.62 +/- 1.14 mu M, and 8.07 +/- 1.36 mu M, respectively, when compared with erlotinib (IC50 = 17.86 +/- 3.22 mu M, 19.41 +/- 2.38 mu M, and 23.81 +/- 4.17 mu M, respectively). Further mechanistic assays demonstrated that compound 2e enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC50 value of 2.80 +/- 0.52 mu M when compared with erlotinib (IC50 = 0.04 +/- 0.01 mu M). However, compound 2e did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound 2e emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound 2e is a promising EGFR inhibitor that warrants further clinical investigations.