Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d]pyridazine bearing 3,4,5-trimethoxyphenyl
- 179 Downloads
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%).
KeywordsiNOS COX-2 Anti-inflammatory Neuroprotective Pyrazole derivatives Pyrazolo[3,4-d]pyridazine derivatives
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.
- Chen WF, Chakraborty C, Sung CS, Feng CW, Jean YH, Lin YY, Hung HC, Huang TY, Huang SY, Su TM, Sung PJ, Sheu JH, Wen ZH (2012) Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: a promising candidate for the treatment of Parkinson’s disease. Naunyn-Schmiedeberg’s Arch Pharmacol 385(3):265–275CrossRefGoogle Scholar
- Garn H, Bahn S, Baune BT, Binder EB, BisgaardH, Chatila TA, Chavakis T, Culmsee C, Dannlowski U, Gay S, Gern J, Haahtela T, Kircher T, Muller-Ladner U, Neurath MF, Preissner KT, Reinhardt C, Rook G, Russell S, Schmeck B, Stappenbeck T, Steinhoff U, van Os J, Weiss S, Zemlin M, Renz H (2016) Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation. J Allergy Clin Immunol 138(1):47–56CrossRefPubMedGoogle Scholar
- Gokhan-Kelekci N, Yabanoglu S, Kupeli E, Salgin U, Ozgen O, Ucar G, Yesilada E, Kendi E, Yesilada A, Bilgin AA (2007) A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics. Bioorg Med Chem 15(17):5775–5786CrossRefPubMedGoogle Scholar
- Jayaraj RL, Tamilselvam K, Manivasagam T, Elangovan N (2013) Neuroprotective effect of CNB-001, a novel pyrazole derivative of curcumin on biochemical and apoptotic markers against rotenone-induced SK-N-SH cellular model of Parkinson’s disease. J Mol Neurosci 51(3):863–870CrossRefPubMedGoogle Scholar
- Myatt JW, Healy MP, Bravi GS, Billinton A, Johnson CN, Matthews KL, Jandu KS, Meng W, Hersey A, Livermore DG, Douault CB, Witherington J, Bit RA, Rowedder JE, Brown JD, Clayton NM (2010) Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain. Bioorg Med Chem Lett 20(15):4683–4688CrossRefPubMedGoogle Scholar