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
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