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

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2201407. doi: 10.1080/14756366.2023.2201407.
Waleed A Badawi  1 ,  Mahmoud Rashed  2 ,  Alessio Nocentini  3  4 ,  Alessandro Bonardi  3  4 ,  Mohammad M Abd-Alhaseeb  5 ,  Sara T Al-Rashood  6 ,  Giri Babu Veerakanellore  7 ,  Taghreed A Majrashi  8 ,  Eslam B Elkaeed  9 ,  Bahaa Elgendy  7  10 ,  Paola Gratteri  3 ,  Claudiu T Supuran  4 ,  Wagdy M Eldehna  11 ,  Mohamed Elagawany  1
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Damanhour University, Damanhour, Buhaira, Egypt.
  • 2. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
  • 3. Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Sesto Fiorentino, Italy.
  • 4. Department of Neurofarba, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Firenze, Sesto Fiorentino, Italy.
  • 5. Department of Pharmacology and Toxicology, Damanhour University, Damanhour, Buhaira, Egypt.
  • 6. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
  • 7. Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, MO, USA.
  • 8. Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.
  • 9. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
  • 10. Chemistry Department, Faculty of Science, Benha University, Benha, Egypt.
  • 11. Department of Pharmaceutical Chemistry, Kafrelsheikh University, Kafrelsheikh, Egypt.
PMID: 37078173 DOI: 10.1080/14756366.2023.2201407
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.

Keywords
Analgesic; Molecular modelling; Pyridazinone; Sulphonates; Synthesis.
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