2. Academic Validation
  3. Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action

  • RSC Med Chem. 2023 Mar 16;14(4):734-744. doi: 10.1039/d3md00038a.
Fatma A M Mohamed 1,  Saleha Y M Alakilli 2,  Eman Fawzy El Azab 1 3,  Faris A M Baawad 4,  Esraa Ibrahim A Shaaban 5,  Heba Abu Alrub 1,  Omnia Hendawy 6 7,  Hesham A M Gomaa 6,  Adel G Bakr 8,  Mostafa H Abdelrahman 9,  Laurent Trembleau 10,  Anber F Mohammed 11,  Bahaa G M Youssif 11
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University Al-Qurayyat 77454 Saudi Arabia fatmaahmed@ju.edu.sa.
  • 2 Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University Jeddah 23761 Saudi Arabia.
  • 3 Biochemistry Department, Faculty of Science, Alexandria University Alexandria 21511 Egypt.
  • 4 M.B.B.S, Faculty of Medicine, King Abdulaziz University Jeddah 23761 Saudi Arabia.
  • 5 Department of Biochemistry, Graduate; School of Medical Sciences, Nagoya City University Mizuho-cho, Mizuho-ku Nagoya 467-8601 Japan.
  • 6 Department of Pharmacology, College of Pharmacy, Jouf University Sakaka 72341 Aljouf Saudi Arabia.
  • 7 Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University Beni-Suef Egypt.
  • 8 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University Assiut Branch Assiut 71524 Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University Assiut 71524 Egypt.
  • 10 School of Natural and Computing Sciences, University of Aberdeen Meston Building Aberdeen AB243UE UK.
  • 11 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University Assiut 71526 Egypt bgyoussif2@gmail.com +201098294419.
PMID: 37122549 DOI: 10.1039/d3md00038a
Abstract

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four Cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four Cancer cell lines tested, with mean GI50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors.

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