4-(5-Amino-pyrazol-1-yl)benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments

  • Eur J Med Chem. 2023 Mar 15;250:115180. doi: 10.1016/j.ejmech.2023.115180.
Mahmoud A Ragab  1 ,  Wagdy M Eldehna  2 ,  Alessio Nocentini  3 ,  Alessandro Bonardi  3 ,  Hazem E Okda  4 ,  Bahaa Elgendy  5 ,  Tarek S Ibrahim  6 ,  Mohammad M Abd-Alhaseeb  7 ,  Paola Gratteri  8 ,  Claudiu T Supuran  9 ,  Ahmed A Al-Karmalawy  10 ,  Mohamed Elagawany  11
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Buhaira, 22516, Egypt.
  • 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; School of Biotechnology, Badr University in Cairo, Badr City, 11829, Egypt. Electronic address: [email protected].
  • 3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 4. Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and Pharmacy in St. Louis, MO, USA.
  • 5. Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and Pharmacy in St. Louis, MO, USA; Chemistry Department, Faculty of Science, Benha University, Benha, Egypt.
  • 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
  • 7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Buhaira, 22516, Egypt.
  • 8. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 9. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: [email protected].
  • 10. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt.
  • 11. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Buhaira, 22516, Egypt. Electronic address: [email protected].
PMID: 36796297 DOI: 10.1016/j.ejmech.2023.115180
Abstract

In the current medical era, the single target inhibition paradigm of drug discovery has given way to the multi-target design concept. As the most intricate pathological process, inflammation gives rise to a variety of diseases. There are several drawbacks to the single target anti-inflammatory drugs currently available. Herein, we present the design and synthesis of a novel series of 4-(5-amino-pyrazol-1-yl)benzenesulfonamide derivatives (7a-j) with COX-2, 5-LOX and Carbonic Anhydrase (CA) inhibitory activities as potential multi-target anti-inflammatory agents. The pharmacophoric 4-(pyrazol-1-yl)benzenesulfonamide moiety in Celecoxib was used as the core scaffold and different substituted phenyl and 2-thienyl tails were grafted via a hydrazone linker to enhance inhibitory activity against hCA IX and XII isoforms, yielding target pyrazoles 7a-j. All reported pyrazoles were evaluated for their inhibitory activity against COX-1, COX-2, and 5-LOX. Pyrazoles 7a, 7b, and 7j showed the best inhibitory activities against the COX-2 isozyme (IC50 = 49, 60 and 60 nM, respectively) and against 5-LOX (IC50 = 2.4, 1.9, and 2.5 μM, respectively) with excellent SI indices (COX-1/COX-2) of 212.24, 208.33, and 158.33, respectively. In addition, the inhibitory activities of pyrazoles 7a-j were evaluated against four different hCA isoforms I, II, IX, and XII. Both transmembrane hCA IX and XII isoforms were potently inhibited by pyrazoles 7a-j with KI values in the nanomolar range; 13.0-82.1 nM and 5.8-62.0 nM, respectively. Furthermore, pyrazoles 7a and 7b with the highest COX-2 activity and selectivity indices were evaluated in vivo for their analgesic, anti-inflammatory, and ulcerogenic activities. The serum level of the inflammatory mediators was then measured in order to confirm the anti-inflammatory activities of pyrazoles 7a and 7b.

Keywords
Analgesic; Inflammatory mediators; Molecular modeling; Pyrazoles; Ulcerogenic activity.
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