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

Waleed A. Badawi, Mahmoud Rashed, Alessio Nocentini, Alessandro Bonardi, Mohammad M. Abd-Alhaseeb, Sara T. Al-Rashood, Giri Babu Veerakanellore, Taghreed A. Majrashi, Eslam B. Elkaeed, Bahaa Elgendy, Paola Gratteri, Claudiu T. Supuran, Wagdy M. Eldehna, Mohamed Elagawany

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 (5a-c and 7a-f) 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 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, 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 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined.

Original languageEnglish
Article number2201407
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume38
Issue number1
DOIs
StatePublished - 2023

Keywords

  • Analgesic
  • Molecular modelling
  • Pyridazinone
  • Sulphonates
  • Synthesis

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