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

Mahmoud A Ragab; Wagdy M Eldehna; Alessio Nocentini; Alessandro Bonardi; Hazem E Okda; Bahaa Elgendy; Tarek S Ibrahim; Mohammad M Abd-Alhaseeb; Paola Gratteri; Claudiu T Supuran; Ahmed A Al-Karmalawy; Mohamed Elagawany

doi:10.1016/j.ejmech.2023.115180

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. Epub 2023 Feb 3.

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: wagdy2000@gmail.com.
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: claudiu.supuran@unifi.it.
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: elagawany@pharm.dmu.edu.eg.

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 K_I 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.

MeSH terms

Anti-Inflammatory Agents / pharmacology
Benzenesulfonamides
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases* / metabolism
Cyclooxygenase 2
Isoenzymes
Molecular Structure
Pyrazoles / pharmacology
Structure-Activity Relationship

Substances

Carbonic Anhydrases
Cyclooxygenase 2
Carbonic Anhydrase Inhibitors
Isoenzymes
Anti-Inflammatory Agents
Pyrazoles
Carbonic Anhydrase IX