Design, synthesis, biological evaluation and in silico studies of few novel 2-substituted benzothiazole derivatives as potential EGFR inhibitors

Muhammad Mubeen, Suvarna Ganesh Kini, Avinash Kumar, Karkala Sreedhara Ranganath Pai

Research output: Contribution to journalArticle

Abstract

Background: There is a great unmet medical need for new anticancer small molecule therapeutics. Exhaustive literature review suggests that benzothiazole derivatives have good potential to exhibit anticancer activity. Compounds that inhibit the kinase activity of EGFR are of potential interest as new antitumor agent. Objective: To design, synthesize and carry out in silico along with biological evaluation of 2- substituted benzothiazole compounds with EGFR inhibitory activity. Methods: Benzothiazole derivatives designed from molecular docking method for potential EGFR tyrosine kinase inhibition have been synthesized based on the docking results and characterized. Insilico studies were carried out to understand the mode of EGFR enzyme inhibition by our molecules. As a preliminary study, these compounds were first screened for antioxidant activity and then for anticancer activity against MCF-7 cell lines and A549 cell line. Results: Compound B5 showed potent anticancer activity on MCF-7 cell line with IC50 value of 9.7µM and compound B8 showed significant anticancer activity on A549 cell line with IC50 value of 49.7µM in comparison with the standard drug Doxorubicin (IC50 = 1.4µM on MCF-7 and 1.0µM on A549 cell lines). In EGFR inhibitory activity B8 showed maximum activity on A549 cell line by inactivating 69.10% of EGFR phosphorylation and B7 showed maximum activity on MCF-7 cell line by inactivating 41.90% of EGFR phosphorylation in comparison with the reference drug Gefitinib. Molecular dynamics simulation studies suggest that benzothiazole derivative could also bind to allosteric site and inhibit the EGFR enzyme activity. Conclusion: Reported compounds have shown potent anticancer activity through EGFR inhibition by possibly binding at allosteric site.

Original languageEnglish
Pages (from-to)961-971
Number of pages11
JournalLetters in Drug Design and Discovery
Volume16
Issue number8
DOIs
Publication statusPublished - 01-01-2019

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Computer Simulation
MCF-7 Cells
Allosteric Site
Inhibitory Concentration 50
Cell Line
Phosphorylation
Enzymes
Molecular Dynamics Simulation
Pharmaceutical Preparations
Antineoplastic Agents
Protein-Tyrosine Kinases
Doxorubicin
Phosphotransferases
Antioxidants
A549 Cells
benzothiazole
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

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title = "Design, synthesis, biological evaluation and in silico studies of few novel 2-substituted benzothiazole derivatives as potential EGFR inhibitors",
abstract = "Background: There is a great unmet medical need for new anticancer small molecule therapeutics. Exhaustive literature review suggests that benzothiazole derivatives have good potential to exhibit anticancer activity. Compounds that inhibit the kinase activity of EGFR are of potential interest as new antitumor agent. Objective: To design, synthesize and carry out in silico along with biological evaluation of 2- substituted benzothiazole compounds with EGFR inhibitory activity. Methods: Benzothiazole derivatives designed from molecular docking method for potential EGFR tyrosine kinase inhibition have been synthesized based on the docking results and characterized. Insilico studies were carried out to understand the mode of EGFR enzyme inhibition by our molecules. As a preliminary study, these compounds were first screened for antioxidant activity and then for anticancer activity against MCF-7 cell lines and A549 cell line. Results: Compound B5 showed potent anticancer activity on MCF-7 cell line with IC50 value of 9.7µM and compound B8 showed significant anticancer activity on A549 cell line with IC50 value of 49.7µM in comparison with the standard drug Doxorubicin (IC50 = 1.4µM on MCF-7 and 1.0µM on A549 cell lines). In EGFR inhibitory activity B8 showed maximum activity on A549 cell line by inactivating 69.10{\%} of EGFR phosphorylation and B7 showed maximum activity on MCF-7 cell line by inactivating 41.90{\%} of EGFR phosphorylation in comparison with the reference drug Gefitinib. Molecular dynamics simulation studies suggest that benzothiazole derivative could also bind to allosteric site and inhibit the EGFR enzyme activity. Conclusion: Reported compounds have shown potent anticancer activity through EGFR inhibition by possibly binding at allosteric site.",
author = "Muhammad Mubeen and Kini, {Suvarna Ganesh} and Avinash Kumar and Pai, {Karkala Sreedhara Ranganath}",
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AU - Kini, Suvarna Ganesh

AU - Kumar, Avinash

AU - Pai, Karkala Sreedhara Ranganath

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N2 - Background: There is a great unmet medical need for new anticancer small molecule therapeutics. Exhaustive literature review suggests that benzothiazole derivatives have good potential to exhibit anticancer activity. Compounds that inhibit the kinase activity of EGFR are of potential interest as new antitumor agent. Objective: To design, synthesize and carry out in silico along with biological evaluation of 2- substituted benzothiazole compounds with EGFR inhibitory activity. Methods: Benzothiazole derivatives designed from molecular docking method for potential EGFR tyrosine kinase inhibition have been synthesized based on the docking results and characterized. Insilico studies were carried out to understand the mode of EGFR enzyme inhibition by our molecules. As a preliminary study, these compounds were first screened for antioxidant activity and then for anticancer activity against MCF-7 cell lines and A549 cell line. Results: Compound B5 showed potent anticancer activity on MCF-7 cell line with IC50 value of 9.7µM and compound B8 showed significant anticancer activity on A549 cell line with IC50 value of 49.7µM in comparison with the standard drug Doxorubicin (IC50 = 1.4µM on MCF-7 and 1.0µM on A549 cell lines). In EGFR inhibitory activity B8 showed maximum activity on A549 cell line by inactivating 69.10% of EGFR phosphorylation and B7 showed maximum activity on MCF-7 cell line by inactivating 41.90% of EGFR phosphorylation in comparison with the reference drug Gefitinib. Molecular dynamics simulation studies suggest that benzothiazole derivative could also bind to allosteric site and inhibit the EGFR enzyme activity. Conclusion: Reported compounds have shown potent anticancer activity through EGFR inhibition by possibly binding at allosteric site.

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