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

Abstract

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 μM, 9.62 ± 1.14 μM, and 8.07 ± 1.36 μM, respectively, when compared with erlotinib (IC50 = 17.86 ± 3.22 μM, 19.41 ± 2.38 μM, and 23.81 ± 4.17 μM, 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 μM when compared with erlotinib (IC50 = 0.04 ± 0.01 μM). 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.

• Authors: Belgin Sever, Mehlika Dilek Altıntop, Ahmet Özdemir, Gülşen Akalın Çiftçi, Doha E Ellakwa, Hiroshi Tateishi, Mohamed O Radwan, Mahmoud A A Ibrahim, Masami Otsuka, Mikako Fujita, Halil I Ciftci, Taha F S Ali
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 25 Issue 21 (Nov 07 2020) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 33171861 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzothiazoles
• Cyclooxygenase 2 Inhibitors
• Indoles
• Oxadiazoles
• Thiazoles
• Erlotinib Hydrochloride
• Cyclooxygenase 1
• Cyclooxygenase 2
• EGFR protein, human
• ErbB Receptors

Topics

• A549 Cells
• Allosteric Site
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Benzothiazoles (chemistry)
• Catalytic Domain
• Cell Line, Tumor
• Cyclooxygenase 1 (chemistry)
• Cyclooxygenase 2 (chemistry)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Drug Design
• Drug Screening Assays, Antitumor
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride (pharmacology)
• HCT116 Cells
• Humans
• Indoles (pharmacology)
• Inhibitory Concentration 50
• Magnetic Resonance Spectroscopy
• Molecular Docking Simulation
• Molecular Structure
• Oxadiazoles (pharmacology)
• Sheep
• Structure-Activity Relationship
• Thiazoles (chemistry)