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Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1557–1566 | Cite as

Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d]pyridazine bearing 3,4,5-trimethoxyphenyl

  • Mashooq A. Bhat
  • Atallah F. Ahmed
  • Zhi-Hong Wen
  • Mohamed A. Al-Omar
  • Hatem A. Abdel-Aziz
Original Research

Abstract

A new series of 3,4,5-trimethoxyphenyl bearing pyrazole (4a–g) and pyrazolo[3,4-d]pyridazine (5a–g) scaffolds were synthesized in good yield. The newly synthesized compounds were characterized on the basis of elemental and spectroscopic analyses. Their inhibitory activity against the pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 proteins expression in lipopolysaccharide-stimulated murine RAW 264.7 macrophages were assessed and showed various potencies. All pyrazolo[3,4-d]pyridazine compounds (5a–g) strongly down regulated lipopolysaccharide inducible nitric oxide synthase expression to the range of 20.3 ± 0.6–51.3 ± 3.5% relative to the bioactive pyrazole derivatives 4b, 4c, 4e and 4g. With the exception of inactive compounds 4c and 4d, all other synthesized compounds inhibited cyclooxygenase-2 expression below 100% in the lipopolysaccharide-stimulated cells, which being declined maximally to 42.8 ± 1.4% by one of the pyrazolo[3,4-d]pyridazine compounds (5d). Moreover, the neuroprotective activity of the less cytotoxic compounds 4b, (4e–g) and (5a–g) were evaluated against 6-hydroxydopamine (6-OHDA)-induced neuroblastoma SH-SY5Y cell death and exhibited significant (p < 0.05) cell protection. The pyrazolo[3,4-d]pyridazine compound (5e) exhibited more than 100% of relative neuroprotection (110.7 ± 4.3%) with an additional advantage of having the highest cell viability index (107.2 ± 2.9%).

Keywords

iNOS COX-2 Anti-inflammatory Neuroprotective Pyrazole derivatives Pyrazolo[3,4-d]pyridazine derivatives 

Notes

Acknowledgements

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research group no. (RG 1435–006).

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Department of Pharmacognosy, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of Pharmacognosy, Faculty of PharmacyMansoura UniversityMansouraEgypt
  4. 4.Department of Marine Biotechnology and ResourcesNational Sun Yat-sen UniversityKaohsiungTaiwan
  5. 5.Applied Organic Chemistry DepartmentNational Research CentreDokkiEgypt

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