Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor critical in regulating inflammation, pain, and physiological functions such as wound healing and epithelial barrier integrity. Chronic PAR2 activation contributes to numerous inflammatory and immune diseases, including inflammatory bowel disease (IBD), asthma, and arthritis, and plays a role in tumor progression by promoting proliferation, angiogenesis, and metastasis. Despite its biological importance, no drugs directly targeting PAR2 are commercially available, highlighting an urgent need for effective therapeutic solutions.
In this study, we designed and synthesized novel triazole peptide derivatives with anti-inflammatory properties as PAR2 antagonists. Using environmentally sustainable methodologies, we optimized reaction conditions to achieve substantial reductions in synthesis time and increased yields. The synthesis of benzyl azides was reduced to 15 minutes (from 3–12 hours), and triazole formation was completed in 5 minutes, lowering the total reaction time from 15 hours to 25 minutes. Employing water as a solvent ensured alignment with green chemistry principles.
The synthesized triazole derivatives demonstrated yields over 62%, and peptide-coupled products exceeded 77%. Structural confirmation was performed using ¹H NMR, ¹³C NMR, and HR-MS. These results underscore the potential of these derivatives as PAR2 antagonists, offering a foundation for addressing inflammation-related and other pathological conditions.
Future efforts will focus on evaluating cell viability, assessing in vitro PAR2 inhibitory activity through Ca²⁺ mobilization assays, and conducting 3D-QSAR analyses to elucidate structure-activity relationships. This work represents a significant step forward in the development of novel therapies for PAR2-related diseases.