Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity

Fatma A M Mohamed; Hesham A M Gomaa; O M Hendawy; Asmaa T Ali; Hatem S Farghaly; Ahmed M Gouda; Ahmed H Abdelazeem; Mostafa H Abdelrahman; Laurent Trembleau; Bahaa G M Youssif

doi:10.1016/j.bioorg.2021.104960

Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity

Bioorg Chem. 2021 Jul:112:104960. doi: 10.1016/j.bioorg.2021.104960. Epub 2021 May 1.

Authors

Affiliations

¹ Clinical Laboratory Science Department, College of Applied Medical Sciences, Jouf University, Aljouf 72341, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, Alexandria-21321, Egypt.
² Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
³ Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University, Egypt.
⁴ Biochemistry Department, Faculty of Pharmacy, Nahda University, Beni-Suef 62511, Egypt.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁶ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
⁷ School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB243UE, United Kingdom.
⁸ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: bahaa.youssif@pharm.aun.edu.eg.

PMID: 34020242
DOI: 10.1016/j.bioorg.2021.104960

Abstract

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.

Keywords: Antiproliferative; Apoptosis; Caspases; EGFR; Indole.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
EGFR protein, human
ErbB Receptors