Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights

Abstract

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (<b>5a-c</b> and <b>7a-f</b>) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines <b>5a-c</b>. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates <b>7a-f</b>, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 <i>h</i>CA isoforms <b>(I</b>, <b>II</b>, <b>IX</b>, and <b>XII</b>), as well as against COX-1/2, and 5-LOX. Furthermore, <i>in vivo</i> anti-inflammatory and analgesic effects of pyridazinones <b>7a</b> and <b>7b</b> were examined.