3,4-Dihydropyrimidin-2(1H)-one C5 Amides as Inhibitors of TNF alpha Production: Synthesis, Biological Evaluation and Molecular Modeling

作者：Ebadi Ahmad; Khoshneviszadeh Mehdi; Javidnia Katayoun; Ghahremani Mohammad Hossein; Firuzi Omidreza^*; Miri Ramin^*

来源：Letters in Drug Design and Discovery, 2017, 14(8): 885-897.

DOI：10.2174/1570180814666170306120235

• Inflammation
• rheumatoid arthritis
• dihydropyrimidinone
• docking
• molecular dynamic simulations
• molecular modeling

Background: Regulation of pro-inflammatory cytokines especially TNF alpha can have therapeutic effects in inflammatory diseases and this approach has attracted much attention for drug discovery for diseases such as rheumatoid arthritis.
Objective: In the present contribution, 16 derivatives of 3,4-dihydropyrimidin-2(1H)-one(thione) C5 amide were synthesized and their anti-inflammatory activities were investigated.
Methods: We synthesized 3,4-dihydropyrimidin-2(1H)-one(thione) C5 amide derivatives according to Biginelli method. Inhibitory effect of newly synthesized derivatives was evaluated on TNF-alpha production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs).
Results: Most of these compounds demonstrated good inhibition of TNF-alpha production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs). Compounds 6k and 6c showed the highest levels of TNF alpha inhibition (74.9% and 72.2% at 50 mu M, respectively). Molecular modeling study revealed that compound 6k formed a stable complex with the active site of p38 alpha MAPK.
Conclusion: The common structural feature of two most potent compounds was the presence of 6-ethoxybenzothiazol moiety on the carbamoyl group at position 5 of the DHPM ring. The findings of this study provide evidence that DHPM derivatives might be considered as promising compounds for the discovery of novel anti-cytokine agents. Amino acid decomposition analysis showed that DHPM scaffold had essential pharmacophore components of p38 alpha MAPK inhibitors.

• 出版日期2017