Synthesis and biological evaluation of clovamide analogues as potent anti-neuroinflammatory agents in vitro and in vivo

A series of clovamide analogues, namely, 1a-13a and 1b-13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b-8b) showed NO inhibition with no or weak cytotoxicity (CC₅₀ > 100 μM), especially 4b, and showed an IC₅₀ value of 2.67 μM. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO Synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC₅₀ values ranging from 1.01 μM to 29.23 μM 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy.

Clovamide analogues; Neuroinflammation; Nitric oxide; Parkinson's disease; iNOS inhibitor.