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* and Ramin Miri*
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
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
