Design, synthesis and biological evaluation of pyranocarbazole derivatives against Alzheimer’s disease, with antioxidant, neuroprotective and cognition enhancing properties

Abstract

A series of novel pyranocarbazole alkaloids were designed and synthesized as derivatives of Claulansine F and CZ-7. Some of the compounds showed strong neuroprotective effects and anti-lipid peroxidation capacity. Among these compounds, 10b, introduced leucine at the C-3 position of pyranocarbazole, was the most active in inhibiting the programmed death of SH-SY5Y cells. This compound exhibited stronger free radical scavenging activity than Edaravone. Furthermore, 10b could penetrate the blood–brain barrier (BBB). More importantly, 10b showed a tendency of improvement in learning and memory in the dose range of 10–40 mg/kg. The research on mechanisms indicated that 10b could reduce oxidative stress in the brain of Aβ25-35-intoxicated mice, and then improve the cognitive function of Aβ25-35-intoxicated mice. Our findings suggest that 10b may be promising for further evaluation as an intervention for Alzheimer’s Disease.