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%).