Development of 2,4‐Substituted Thiazoles as Dual Inhibitors of Inflammation and Breast‐Cancer Progression

Breast cancer remains a major cause of cancer-related mortality worldwide, with chronic inflammation recognized as a key contributor to its initiation and progression. This study aimed to develop 2,4-substituted thiazoles with dual anti-inflammatory and anticancer potential. A series of 20 2,4-substituted thiazoles 3(a-t) was synthesized and evaluated for biological efficacy. Antioxidant screening revealed compound 3t showed strong inhibition (IC₅₀ = 26.53 ± 0.16 µg/mL). Anti-inflammatory protein denaturation assays demonstrated significant inhibition by compounds 3p and 3r (IC₅₀ = 6.50 ± 0.89 and 10.72 ± 4.36 µg/mL). Cytotoxicity screening against MCF-7 breast cancer cells showed 3r had higher antiproliferative potency (IC₅₀ = 17.44 µg/mL) than 3p, confirmed by cell cycle analysis and dual fluorescent staining, indicating mild apoptosis and suppressed proliferation. In silico ADME, drug-likeness, and network pharmacology analyses supported favorable pharmacokinetic profiles and identified potential molecular targets. Molecular docking revealed strong binding interactions. Overall, compound 4-(2-(2-((1-benzyl-1H-indol-3-yl)methylene)hydrazinyl)thiazol-4-yl)benzonitrile (3r) emerges as a promising multifunctional lead, highlighting the potential of 2,4-substituted thiazoles scaffolds in targeting inflammation-associated breast cancer. The novelty of this work lies in demonstrating the dual efficacy of these hybrids in modulating inflammatory and proliferative pathways, guiding future mechanistic and in vivo investigations.