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

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

Volume: 14 Issue: 8

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

Affiliation:

• Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz,Iran

• Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz,Iran

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

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

Cite this article as:

Ebadi Ahmad, Khoshneviszadeh Mehdi, Javidnia Katayoun, Ghahremani Hossein Mohammad, Firuzi Omidreza*, Miri Ramin*, 3,4-Dihydropyrimidin-2(1H)-one C5 Amides as Inhibitors of T NFα Production: Synthesis, Biological Evaluation and Molecular Modeling, Letters in Drug Design & Discovery 2017; 14 (8) . https://dx.doi.org/10.2174/1570180814666170306120235

DOI https://dx.doi.org/10.2174/1570180814666170306120235	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X