A novel series of dihydropyrimidine/sulphonamide hybrids 3a–j with antiinflammatory
properties have been developed and tested as dual mPGES-1/5-
LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j
were the most effective dual inhibitors of mPGES-1 and 5-LOX activities.
Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 μM
and 1.98 μM, respectively. In vivo, anti-inflammatory studies demonstrated that
compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with
EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib
after the first hour but exhibited stronger anti-inflammatory effects than
celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j
significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α,
and IL-6) with gastrointestinal safety profiles. Molecular docking simulations
explored the most potent derivatives’ binding affinities and interaction patterns
within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is
a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that
deserves further preclinical investigation.