Synthesis, physicochemical characterization, and investigation of anti-inflammatory activity of water-soluble PEGylated 1,2,4-Triazoles

A series of water-soluble PEGylated 1,2,4-triazoles 5 - 8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1 H -1,2,4-triazole-3-carboxylates 1 . All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1 H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1 H -1,2,4-triazole-3-car- boxylates. For SAR study, all PEGylated 1,2,4-triazoles 5 - 8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC 50 = 3.42 - 7.81 mu M). Moreover, the western blot result showed PEGylated 1,2,4triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX -2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a - d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d . Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4triazole 7d more effectively decreased the inflammatory response in edema and COX -2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.