Synthesis and Evaluation of Pyridinyltriazoles as Inhibitors of p۳۸ MAP Kinase

Objective(s) Inhibitors of p۳۸ MAP kinase are considered as suitable target in the treatment of inflammatory diseases such as rheumatoid arthritis and bowel inflammatory diseases. The development of ۵-alkylthio-۱-aryl-۲-(۴-pyridinyl) triazoles as inhibitors of p۳۸ MAP kinase is described. These are analogues of ۴- pyridinyl imidazole p۳۸ MAP kinase inhibitor reported by Merck Research Laboratories, in which imidazole ring has been replaced with triazole. Materials and Methods Reaction of pyridine-۴-carboxylic acid hydrazide ۱ and arylisothiocyanate (۲a, b) gave the intermediate thiourea derivative ۳a, b (Figure ۲). Refluxing  of the latter in aqueous saturated sodium carbonate gave ۱-aryl-۵-mercapto-۲-(۴-pyridinyl) triazoles ۴a, b. Treatment of ۴a, b with alkyl iodide afforded the desired ۵-alkylthio-۱-aryl-۲-(۴-pyridinyl) triazoles (۵a-d). P۳۸ MAP kinase inhibitory activity of the synthesized compounds was evaluated in vitro by ELISA method and also by molecular docking. Results Compound ۵c at ۱ µM concentration and compound ۵d at ۱ µM and ۱۰ µM significantly inhibited the p۳۸ phosphorylation. These inhibitory effects are equal to those of standard compound SB۲۰۲۱۹۰ and no significant differences were observed. Conclusion We demonstrated that both tested compounds have inhibitory effect on p۳۸ MAP kinase and we did not find significant difference between their inhibitory effects and those of standard inhibitor SB۲۰۲۱۹۰.

Keywords:

Inhibitors , p۳۸ MAP kinase , Pyridinylimidazoles