2. Academic Validation
  3. Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation

  • Bioorg Chem. 2024 Nov:152:107727. doi: 10.1016/j.bioorg.2024.107727.
Mohamed K Elgohary 1,  Mahmoud F Abo-Ashour 2,  Soha R Abd El Hadi 3,  Mahmoud A El Hassab 4,  Mohammed E Abo-El Fetoh 5,  Hassan Afify 5,  Hatem A Abdel-Aziz 6,  Sahar M Abou-Seri 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, El Saleheya El Gadida University, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt. Electronic address: soha-ramadan@eru.edu.eg.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, Egypt.
  • 5 Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt.
  • 6 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: ha.abdel-aziz@nrc.sci.eg.
  • 7 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
PMID: 39167872 DOI: 10.1016/j.bioorg.2024.107727
Abstract

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein-ligand interactions at COX-2 active sites indicative of therapeutic potential.

Keywords

ADME; COX-2; Inflammation; Phenoxy acetic acid; Pyrazoline.

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