Sulfonamide-Pyrazole derivatives as next-generation Cyclooxygenase-2 enzyme inhibitors: From molecular design to in vivo efficacy

Mohamed K Elgohary; Mahmoud S Elkotamy; Mahmoud Abdelrahman Alkabbani; Mahmoud A El Hassab; Sara T Al-Rashood; Faizah A Binjubair; Marwa Alsulaimany; Hazem A Ghabbour; Wagdy M Eldehna; Hatem A Abdel-Aziz

doi:10.1016/j.ijbiomac.2024.139170

Sulfonamide-Pyrazole derivatives as next-generation Cyclooxygenase-2 enzyme inhibitors: From molecular design to in vivo efficacy

Int J Biol Macromol. 2024 Dec 28:293:139170. doi: 10.1016/j.ijbiomac.2024.139170. Online ahead of print.

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt. Electronic address: mohamed-elgohary@eru.edu.eg.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
³ Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, Egypt.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁶ Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia.
⁷ School of Health and Biomedical Sciences, RMIT University, Melbourne 3083, Australia.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
⁹ Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: hatem_741@yahoo.com.

PMID: 39736293
DOI: 10.1016/j.ijbiomac.2024.139170

Abstract

The current research focuses on the design and synthesis of celecoxib analogues incorporating sulphonamide and pyrazole moieties (4, 5, 6a-e, and 7a-f) with the aim of achieving a broad range of COX-2 selectivity in vitro. Among these, compounds 6b-d, 7a, 7e, and 7d exhibited potent inhibition, with IC₅₀ values ranging between 0.05 and 0.08 μM, and were selected for in vivo evaluation using the formalin-induced paw edema model. To further assess the safety profile of compound 6d, a histopathological examination of paw tissue was conducted alongside routine blood analyses evaluating key liver and kidney function parameters, including creatinine, urea, AST, and ALT levels. The results indicated normal profiles, comparable to reference drugs celecoxib and indomethacin. Additionally, compound 6d was evaluated for its effect on inflammatory biomarkers using ELISA assays. Markedly, 6d elicited a remarkable reduction in TNF-α (71.43 %) and PGE₂ (77.11 %) levels, surpassing the effects of both celecoxib and indomethacin, confirming its potent anti-inflammatory properties. In terms of analgesic activity, Importantly, cardiac toxicity assessment revealed no adverse effects associated with compound 6d. Finally, compound 6d underwent in silico analysis, including molecular docking and molecular dynamics simulations, which confirmed its selective interaction with the COX-2 active site and favorable free insertion into the selectivity side pocket.

Keywords: In-vivo study; Molecular dynamics; Safety profiling.