Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition

Abstract

A novel series of dihydropyrimidine/sulphonamide hybrids <b>3a-j</b> with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. <i>In vitro</i> assay, results showed that compounds <b>3c</b>, <b>3e</b>, <b>3h</b>, and <b>3j</b> were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound <b>3j</b> was the most potent dual inhibitor with IC₅₀ values of 0.92 µM and 1.98 µM, respectively. <i>In vivo,</i> anti-inflammatory studies demonstrated that compounds <b>3c</b>, <b>3e</b>, <b>3h,</b> and <b>3e</b> had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds <b>3e</b> and <b>3j</b> were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds <b>3e</b> and <b>3j</b> 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 <b>3j</b> is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.