Synthesis of Indole-Linked Thiadiazoles and their Anticancer Action against Triple-Negative Breast Cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Computational Chemistry

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to high rates of metastasis, heterogeneity, and relapse.
• Current treatment options for TNBC are limited, necessitating the development of novel chemotherapeutic interventions.

Purpose of the Study:

• To synthesize and evaluate the antiproliferative potential of novel indole-endowed thiadiazole derivatives against the MDA-MB-231 triple-negative breast cancer cell line.
• To investigate the molecular interactions of these compounds with the EGFR receptor and assess their drug-likeness.

Main Methods:

• Synthesis of indole-endowed thiadiazole derivatives.
• In-vitro antiproliferative activity assessment using cell viability assays (MDA-MB-231 cell line).
• Molecular docking studies against the EGFR receptor (PDB ID: 3POZ).
• In-silico pharmacokinetic and DFT-based electronic property evaluations.

Main Results:

• Compound 4h exhibited the most potent anticancer activity with an IC50 of 0.43 μM.
• The synthesized compounds demonstrated strong docking competency with the EGFR receptor, comparable to the known ligand TAK-285.
• In-silico studies indicated favorable pharmacokinetic profiles and electronic properties, suggesting good biochemical reactivity and drug potential.

Conclusions:

• Indole-endowed thiadiazole derivatives show significant promise as potential therapeutic agents for triple-negative breast cancer.
• Compound 4h is identified as a lead candidate for further development in TNBC treatment.
• The study highlights the potential of these novel conjugates in addressing the unmet needs in TNBC therapy.