3,4-Dihydropyrimidin-2(1H)-One C5 Amides As Inhibitors of T Nfα Production: Synthesis, Biological Evaluation and Molecular Modeling Publisher



Ebadi A¹ ; Khoshneviszadeh M^{2, 3} ; Javidnia K^{2, 3} ; Ghahremani MH⁴ ; Firuzi O² ; Miri R^{2, 3} Show Affiliations
Source: Letters in Drug Design and Discovery Published:2017

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. © 2017 Bentham Science Publishers.