Synthesis and Evaluation of Pyridinyltriazoles as Inhibitors of p38 MAP Kinase

Document Type : Original Article

Authors

1 Pharmaceutical Sciences Research Centre, Mashhad University of Medical sciences Mashhad, Iran

2 Medical Toxicology Research Centre, Mashhad University of Medical Sciences Mashhad, Iran

3 School of Pharmacy, Mashhad University of Medical Sciences Mashhad, Iran

4 Biotechnology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s)
Inhibitors of p38 MAP kinase are considered as suitable target in the treatment of inflammatory diseases such as rheumatoid arthritis and bowel inflammatory diseases. The development of 5-alkylthio-1-aryl-2-(4-pyridinyl) triazoles as inhibitors of p38 MAP kinase is described. These are analogues of 4- pyridinyl imidazole p38 MAP kinase inhibitor reported by Merck Research Laboratories, in which imidazole ring has been replaced with triazole.
Materials and Methods
Reaction of pyridine-4-carboxylic acid hydrazide 1 and arylisothiocyanate (2a, b) gave the intermediate thiourea derivative 3a, b (Figure 2). Refluxing  of the latter in aqueous saturated sodium carbonate gave 1-aryl-5-mercapto-2-(4-pyridinyl) triazoles 4a, b. Treatment of 4a, b with alkyl iodide afforded the desired 5-alkylthio-1-aryl-2-(4-pyridinyl) triazoles (5a-d). P38 MAP kinase inhibitory activity of the synthesized compounds was evaluated in vitro by ELISA method and also by molecular docking.
Results
Compound 5c at 1 µM concentration and compound 5d at 1 µM and 10 µM significantly inhibited the p38 phosphorylation. These inhibitory effects are equal to those of standard compound SB202190 and no significant differences were observed.
Conclusion
We demonstrated that both tested compounds have inhibitory effect on p38 MAP kinase and we did not find significant difference between their inhibitory effects and those of standard inhibitor SB202190.

Keywords

References

1. Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell .Res 2005; 15: 11-18.
2. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 2000; 47: 185-201.
3. Rincon M, Flavell RA, Davis RA. The JNK and p38 MAP kinase signaling pathways in T cell-mediated immune responses. Free Radic Biol Med  2000; 28:1328-1337.
4. Saklatvala J. The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol 2004; 4: 372-377.
5. Bolos J. Structure-activity relationships of p38 mitogen-activated protein kinase inhibitors. Mini Rev Med Chem  2005; 5:857-868.
6. Johnson GV, Bailey CD. The p38 MAP kinase signaling pathway in Alzheimer's disease. Exp Neurol  2003; 183:263-268.
7. Stelmach JE, Liu L, Patel SB, Pivnichny JV, Scapin G, Singh S, et al. Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003; 13:277-280.
8. Mayor F Jr, Jurado-Pueyo M, Campos PM, Murga C. Interfering with MAP kinase docking interactions: implications and perspective for the p38 route. Cell Cycle 2007; 6:528-533.
9. Murali Dhar TG, Wrobleski ST, Lin S, Furch JA, Nirschl DS, Fan Y, et al. Synthesis and SAR of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds. Bioorg Med Chem Lett 2007; 17: 5019-5024.
10. Ziegler K, Hauser DR, Unger A, Albrecht W, Laufer SA. 2-Acylaminopyridin-4-ylimidazoles as p38 MAP kinase inhibitors: Design, synthesis, and biological and metabolic evaluations. Chem Med Chem 2009; 4: 1939-1948.
11. Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, et al.  Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem 1997; 5:49-64.
 

Files

Share

How to cite

Statistics