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

Author(s): Ahmad Ebadi, Mehdi Khoshneviszadeh, Katayoun Javidnia, Mohammad Hossein Ghahremani, Omidreza Firuzi*, Ramin Miri*

Journal Name: Letters in Drug Design & Discovery

Volume 14 , Issue 8 , 2017

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Graphical Abstract:


Background: Regulation of pro-inflammatory cytokines especially TNFα 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-α production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs).

Results: Most of these compounds demonstrated good inhibition of TNF-α production in lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMCs). Compounds 6k and 6c showed the highest levels of TNFα inhibition (74.9% and 72.2% at 50 μM, respectively). Molecular modeling study revealed that compound 6k formed a stable complex with the active site of p38α 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 p38α MAPK inhibitors

Keywords: Inflammation, rheumatoid arthritis, dihydropyrimidinone, docking, molecular dynamic simulations, molecular modeling.

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Article Details

Year: 2017
Published on: 19 July, 2017
Page: [885 - 897]
Pages: 13
DOI: 10.2174/1570180814666170306120235
Price: $65

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