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* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.
Original languageEnglish
Article number104960
Number of pages14
JournalBioorganic Chemistry
Volume112
Early online date1 May 2021
DOIs
Publication statusPublished - Jul 2021

Keywords

  • Indole
  • Antiproliferative
  • EGFR
  • Caspases
  • Apoptosis

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