Synthesis and biological evaluation of lappaconitine analogues as potential anti-neuroinflammatory agents by side chain modification and scaffold hopping strategy.

Neuroinflammation mediated by microglia is widely recognized as a key pathophysiological mechanism in neurodegenerative diseases. Lappaconitine (LA) is a natural C18-diterpenoid alkaloid isolated from Aconitum sinomontanum Nakai, and previous study showed that LA and its derivatives inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. However, the anti-neuroinflammatory effects of LA and its derivatives on microglia are still not clear. Here, LA analogues were designed and synthesized, and the anti-neuroinflammatory activity of the synthesized compounds was screened using LPS-induced overexpression of NO in BV-2 microglia. The screening results showed that compound 10 displayed the highest ability to inhibit NO production (IC50 = 9.98 ± 1.6 µM). Mechanistic investigations revealed that compound 10 attenuated LPS-activated neuroinflammation through suppression of TLR4/MyD88/NF-κB pathway in BV-2 microglia. Acute toxicity assays showed that compound 10 (LD50 = 508.1 mg/kg) was safer relative to LA (LD50 = 30.6 mg/kg). Collectively, our findings show that compound 10 could have potential as anti-neuroinflammatory agents.