2. Academic Validation
  3. Exploration of anti-inflammatory activity of pyrazolo[3,4-d]pyrimidine/1,2,4-oxadiazole hybrids as COX-2, 5-LOX and NO release inhibitors: Design, synthesis, in silico and in vivo studies

Exploration of anti-inflammatory activity of pyrazolo[3,4-d]pyrimidine/1,2,4-oxadiazole hybrids as COX-2, 5-LOX and NO release inhibitors: Design, synthesis, in silico and in vivo studies

  • Bioorg Chem. 2025 Mar:156:108181. doi: 10.1016/j.bioorg.2025.108181.
Marwa A Aziz 1,  Ibrahim M Salem 2,  Mohammed A Al-Awadh 3,  Abdulrahman S Alharbi 4,  Deiaa E Elsayed Abouzed 5,  Rasha M Allam 6,  Osama A A Ahmed 7,  Tarek S Ibrahim 3,  Gamal El-Din A Abuo-Rahma 8,  Mamdouh F A Mohamed 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519 Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New Assiut City, Assiut 71515, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 4 Department of Chemistry, College of Science and Humanities-Dawadmi, Shaqra University, Saudi Arabia.
  • 5 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
  • 6 Pharmacology Department, Medical Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
  • 7 Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, 21589 Jeddah, Saudi Arabia; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 8 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519 Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address: mamdouh.fawzi@pharm.sohag.edu.eg.
PMID: 39889555 DOI: 10.1016/j.bioorg.2025.108181
Abstract

New pyrazolo[3,4-d]pyrimidine derivatives 7a-h and 8a-h were synthesized and evaluated for their in vitro inhibitory potential against COX-1, COX-2, 5-LOX along with the NO release inhibitory activity to assess their anti-inflammatory potential. Most compounds confered inhibitory activity at a micromolar level and exhibited prominent selectivity towards COX-2 especially in the 8a-h series. The most useful compound 8e as a COX-2/5-LOX dual inhibitor, exhibited IC50 results of; 1.837 µM for COX-2, 2.662 µM for 5-LOX with an acceptable NO release inhibition rate of 66.02 %. Compounds 7e, 7f, 8e and 8f proved their efficiency as 5-LOX/NO release dual inhibitors; with IC50 values of 2.833, 1.952, 2.662 and 1.573 µM, respectively for 5-LOX biotarget, and with superior NO inhibitory ratio of 73.85, 65.57, 66.02 and 72.28 %, respectively. The in vivo anti-inflammatory assay explored that 7e is the most effective with minimal gastric ulceration prevalence. Molecular docking in the active site of both COX-2 and 5-LOX showed that, the most active 8e and 7e are correctly oriented inside the COX-2 binding pocket with unique binding mode independently on the reference celecoxib. Also, they demonstrated superior binding affinities to the 5-LOX Enzyme over both the Zileuton as a reference drug and the normal ligand 30Z. The stability of the complex formed between the most promising candidates 7e or 8e with the COX-2 and 5-LOX active sites, was considered using a typical atomistic 100 ns dynamic simulation study. Investigation of the SAR revealed the importance of both the sulfonamide group in the 8a-h series and the substituents of the 3-phenyl ring tethered on the 1,2,4-oxadiazole core.

Keywords

1,2,4-Oxadiazole; 5-Lipoxygenase; Anti-inflammatory; Cyclooxygenase; Healthcare; Nitric oxide; Pyrazolo[3,4-d]pyrimidines.

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