2. Academic Validation
  3. Design and synthesis of novel diclofenac-based quinazoline derivatives enhancing cisplatin and radiation impacts via MyD88 and COX-2/PGE2 modulation

Design and synthesis of novel diclofenac-based quinazoline derivatives enhancing cisplatin and radiation impacts via MyD88 and COX-2/PGE2 modulation

  • Eur J Med Chem. 2025 Nov 15:298:117997. doi: 10.1016/j.ejmech.2025.117997.
Mostafa M Ghorab 1,  Mostafa G M El-Gazzar 2,  Aiten M Soliman 3,  Fatma Y Abdou 4,  Walaa A El-Sabbagh 5
Affiliations

Affiliations

  • 1 Drug Chemistry Lab, Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, 11787, Egypt. Electronic address: mmsghorab@yahoo.com.
  • 2 Drug Chemistry Lab, Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, 11787, Egypt.
  • 3 Drug Chemistry Lab, Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, 11787, Egypt. Electronic address: Aiten_mahmoud@yahoo.com.
  • 4 Pharmacology & Toxicology Lab, Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, 11787, Egypt.
  • 5 Biochemistry Lab, Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, 11787, Egypt.
PMID: 40716177 DOI: 10.1016/j.ejmech.2025.117997
Abstract

In Cancer therapy, inhibition of COX-2/PGE2 as an Adjuvant treatment protocol enhances the effectiveness of chemotherapy and radiotherapy while minimizing adverse effects. Two sets of diclofenac-quinazoline derivatives were designed and synthesized as analgesic and anti-inflammatory agents against cisplatin-induced peripheral neuropathic pain. Compounds 12 and 16 demonstrated dual anti-inflammatory and analgesic properties with low cytotoxicity on normal Vero cells. Compounds 12 and 16 were screened in vitro against the COX-2 enzyme and investigated for their effects on cisplatin/radiation-induced inflammatory state and neuropathy, in comparison to the conventional NSAID, diclofenac. Treatment with compounds 12 and 16 reduced MyD88 expression, a central component of inflammatory and nociceptive aggregation, which resulted in a significant decrease in serum COX-2 and PGE2 levels by 47.29 % & 61.75 % and by 47.78 % & 64.33 %, respectively. Both compounds presented antinociceptive effects in response to thermal and mechanical stimuli, along with the suppression of COX-1 and spinal inflammatory conditions. Beneficial treatment with diclofenac-quinazoline compounds over diclofenac was explored, clearly evident through the reduction of hepato-/renal damage caused by cisplatin and radiation dosing, as shown by biochemical and histopathological monitoring. Molecular docking analysis indicated that compounds 12 and 16 possess favourable interaction profiles and high affinity for COX-2 active site.

Keywords

Anti-inflammatory; Antinociceptive; COX-2; Diclofenac; MyD88; Quinazoline.

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