Exploring Carboxamide Derivatives as Promising Anticancer Agents: Design, In Vitro Evaluation, and Mechanistic...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Cancer Biology

Background:

• Carboxamide derivatives are valuable in anticancer drug discovery due to their target interaction and pharmacological profiles.
• N-substituted indole-2-carboxamides represent a class of compounds with potential as novel anticancer agents.

Purpose of the Study:

• To design, synthesize, and biologically evaluate novel N-substituted 1H-indole-2-carboxamides for anticancer potential.
• To assess the antiproliferative activity and selectivity of synthesized compounds against various cancer cell lines.

Main Methods:

• Synthesis of N-substituted 1H-indole-2-carboxamide library.
• In vitro antiproliferative assays (MTT) against MCF-7, K-562, and HCT-116 cancer cell lines.
• Molecular docking and induced-fit docking against cancer-related targets (Topoisomerase-DNA, PI3Kα, EGFR).
• Principal Component Analysis (PCA) of molecular descriptors.

Main Results:

• Compounds 12, 14, and 4 demonstrated potent cytotoxicity against K-562 leukemia cells (IC50 values ≤ 0.61 µM).
• Compound 10 exhibited significant activity against HCT-116 colon cancer cells (IC50 = 1.01 µM) with high selectivity (SI = 99.4).
• Molecular docking studies revealed favorable binding interactions with key cancer targets, suggesting a mechanism of action.
• PCA indicated promising drug-like and lead-like properties for the synthesized compounds, especially compound 10.

Conclusions:

• N-substituted indole-2-carboxamides are promising scaffolds for anticancer drug development.
• The study validates a multi-disciplinary approach combining synthesis, biological evaluation, and computational modeling for identifying potential drug candidates.
• Further optimization of these compounds holds potential for developing new therapeutic agents against cancer.