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

[ Vol. 14 , Issue. 8 ]

Author(s):

Ahmad Ebadi, Mehdi Khoshneviszadeh, Katayoun Javidnia, Mohammad Hossein Ghahremani, Omidreza Firuzi* and Ramin Miri*   Pages 885 - 897 ( 13 )

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. <p></p> 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. <p></p> 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). <p></p> 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. <p></p> 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 <p></p>

Keywords:

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

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz

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