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  2. Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on bumetanide scaffold

Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on bumetanide scaffold

  • Bioorg Chem. 2020 Jul;100:103878. doi: 10.1016/j.bioorg.2020.103878.
Tarek S Ibrahim 1 Ibrahim M Salem 2 Samia M Mostafa 2 Osama I El-Sabbagh 3 Mohamed K M ElKhamisi 4 Lamees Hegazy 5 Bahaa Elgendy 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address: tmabrahem@kau.edu.sa.
  • 2 Medicinal Chemistry Department, Suez Canal University, Faculty of Pharmacy, Ismailia, Egypt.
  • 3 Medicinal Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
  • 4 Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Egypt.
  • 5 Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA.
  • 6 Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt. Electronic address: bahaa.elgendy@stlcop.edu.
Abstract

Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17 µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and Other Diseases where COX-2 plays important role in their pathophysiology.

Keywords

Anti-inflammatory activity; Benzenesulfonamide; Bumetanide; Pyrazoles; Thiazoles, triazoles.

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