Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction

Abstract

Two series of chalcone/aryl carboximidamide hybrids <b>4a-f</b> and <b>6a-f</b> were synthesised and evaluated for their inhibitory activity against iNOS and PGE2. The most potent derivatives were further checked for their <i>in vivo</i> anti-inflammatory activity utilising carrageenan-induced rat paw oedema model. Compounds <b>4c</b>, <b>4d</b>, <b>6c</b> and <b>6d</b> were proved to be the most effective inhibitors of PGE2, LPS-induced NO production, iNOS activity. Moreover, <b>4c</b>, <b>4d</b>, <b>6c</b> and <b>6d</b> showed significant oedema inhibition ranging from 62.21% to 78.51%, compared to indomethacin (56.27 ± 2.14%) and celecoxib (12.32%). Additionally, <b>4c</b>, <b>6a</b> and <b>6e</b> displayed good COX2 inhibitory activity while <b>4c</b>, <b>6a</b> and <b>6c</b> exhibited the highest 5LOX inhibitory activity. Compounds <b>4c</b>, <b>4d</b>, <b>6c</b> and <b>6d</b> fit nicely into the pocket of iNOS protein (PDB ID: 1r35) <i>via</i> the important amino acid residues. Prediction of physicochemical parameters exhibited that <b>4c</b>, <b>4d</b>, <b>6c</b> and <b>6d</b> had acceptable physicochemical parameters and drug-likeness. The results indicated that chalcone/aryl carboximidamides <b>4c</b>, <b>4d</b>, <b>6c</b> and <b>6d</b>, in particular <b>4d</b> and <b>6d</b>, could be used as promising lead candidates as potent anti-inflammatory agents.