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Novel Pyrazole-3-Cyano-2-Pyridinone Hybrids as Multitarget Anti-Inflammatory Agents: Synthesis, Computational
Bahgat R M Hussein1, Ibrahim M Salem2, Hossameldin A Aziz3,4
1Department of Chemistry, Faculty of Science, Sohag University, Sohag, 82524, Egypt.
Drug Design, Development and Therapy
|April 8, 2026
Summary
Novel pyrazole/3-cyano-2-pyridinone hybrids show potent multi-target anti-inflammatory activity. These compounds effectively inhibit key inflammatory mediators with favorable safety and pharmacokinetic profiles, indicating potential as new drug candidates.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- Multi-target anti-inflammatory agents offer improved efficacy and reduced side effects compared to single-target drugs.
- Developing novel hybrids is a strategic approach to modulate multiple inflammatory pathways simultaneously.
Purpose of the Study:
- To design and synthesize novel pyrazole/3-cyano-2-pyridinone hybrids as multi-target anti-inflammatory agents.
- To evaluate the inhibitory potential of these hybrids against key inflammatory mediators, including nitric oxide (NO), cyclooxygenase (COX), and lipoxygenase (LOX).
Main Methods:
- Synthesis of pyrazole/3-cyano-2-pyridinone hybrids.
- In vitro assays for NO production, iNOS activity, COX-1/COX-2, 5-LOX, 15-LOX, PGE2, and TNF-α inhibition.
- Cytotoxicity assessment using MTT assays.
- Molecular docking, molecular dynamics (MD) simulations, and in silico ADME profiling.
Main Results:
- Compounds 5f, 5g, 5k, and 5m demonstrated significant inhibition of NO production and iNOS activity.
- Compound 5k selectively inhibited COX-2 (IC50 = 0.92 µM) with high selectivity.
- Compound 5f potently inhibited both 5-LOX and 15-LOX, outperforming zileuton.
- Compounds showed low cytotoxicity and favorable predicted pharmacokinetic properties.
Conclusions:
- The synthesized hybrids exhibit promising multi-target anti-inflammatory activity.
- These compounds possess favorable safety and pharmacokinetic profiles, making them potential lead candidates for further drug development.
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