Novel N1 or N9 modified α-carboline analogues as potential ligands in Alzheimer's disease therapy: Synthesis and neurobiological activity evaluation

Abstract

A series of new α-carboline analogues modified at N1 or N9 positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC50 = 1.45 μM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-κB signaling pathway by decreasing the phosphorylation of IκB-α and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H2O2-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC50 of 0.77 μM. Overall, this work provided some lead compounds based on α-carboline used for AD therapy.