Design, synthesis and biological evaluation of 4-(1-(4(sulphanilamide)phenyl)-3-(methyl)-1H-pyrazol-5-yl)dine urea and N-acyl derivatives as a soluble epoxide hydrolase inhibitors

A series of novel sEH inhibitors containing a N-substituted piperidine ring [N-urea (8a-i) (9a-l) and amide derivatives (6a-l) (7a-l)] with pyrazole (a five-membered polar heterocycle) as a pharmacophore lead for sEH inhibition have been designed, synthesized and evaluated as novel analogues to reduce blood pressure elevation and inflammatory roles by acting as sEH inhibitors. The synthesized compound shows varying degree of selectivity towards the sEH enzymes. Particularly compounds 9g and 8h emerged as the most potent sEH inhibitor displaying IC50 values of 0.224 +/- A 0.014 and 0.220 +/- A 0.03 mu M for in vitro sEH inhibition. Molecular docking studies of the designed sEH dual inhibitors are performed using 1ZD5 for sEH as the targeted proteins and which revealed H-bond interactions similar to AUDA. Structure-activity relationships provided useful insights in these classes of compounds and paved the way to design novel analogues with increased potency. Schematic representation of proposed sEH Inhibitors.