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Synthesis and Evaluation of Thiazolyl-indole-2-carboxamide Derivatives as Potent Multitarget Anticancer Agents

Njood M Saadan1, Wahid U Ahmed2, Adnan A Kadi1

  • 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

ACS Omega
|October 14, 2024
PubMed

Insights

Novel indole-2-carboxamide derivatives show potent anticancer activity. Compounds 6i and 6v effectively inhibit cancer cell growth by targeting multiple protein kinases and inducing apoptosis, indicating promise as multitarget cancer therapeutics.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Cancer arises from dysregulated signaling pathways.
  • Multitargeting compounds offer a promising therapeutic strategy.
  • Novel chemical entities are needed to combat cancer progression.

Purpose of the Study:

  • To design, synthesize, and evaluate novel (E/Z)-N-(4-(2-(2-(substituted)hydrazineyl)-2-oxoethyl)thiazol-2-yl)-1H-indole-2-carboxamide derivatives.
  • To identify compounds with potent cytotoxicity against cancer cell lines.
  • To investigate the mechanism of action of promising anticancer agents.

Main Methods:

  • Chemical synthesis of indole-2-carboxamide derivatives (6a-6z).
  • In vitro cytotoxicity assays against various cancer cell lines.
  • Protein kinase inhibition assays (EGFR, HER2, VEGFR-2, CDK2).
  • Cell cycle analysis and apoptosis assays.
  • Molecular docking studies.

Main Results:

  • Compounds 6e, 6i, 6q, 6v, 7a, and 7b demonstrated significant cytotoxicity.
  • Compounds 6i and 6v showed potent activity against MCF-7 cells (IC50 values ~6.1-6.5 μM).
  • These compounds inhibited key cancer-related protein kinases.
  • Cell cycle arrest at G2/M phase and apoptosis induction were observed.
  • Docking studies confirmed favorable binding affinities for 6i and 6v.

Conclusions:

  • The synthesized indole-2-carboxamide derivatives possess significant anticancer potential.
  • Compounds 6i and 6v are identified as lead candidates for further development.
  • These compounds act as multitarget agents, inhibiting key kinases and inducing cell death.
  • Further preclinical studies are warranted to explore their therapeutic efficacy.

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