In our effort to develop effective neuroprotectants as potential treatments for Alzheimer’s disease (AD), hybrid compounds of curcumin and melatonin, two natural products that have been extensively studied in various AD models, were designed, synthesized, and biologically characterized. A lead hybrid compound (7) was discovered to show significant neuroprotection with nanomolar potency (EC₅₀ = 27.60 ± 9.4 nM) in MC65 cells, a cellular AD model. Multiple in vitro assay results established that 7 exhibited moderate inhibitory effects on the production of amyloid-β oligomers (AβOs) in MC65 cells, but not on the aggregation of Aβ species. It also exhibited significant antioxidative properties. Further mechanistic studies demonstrated that 7’s antioxidant effects correlate well with its neuroprotective potency for MC65 cells, and these effects might be due to its interference with the interactions of AβOs within the mitochondria of MC65 cells. Furthermore, 7 was confirmed to cross the blood-brain barrier (BBB) and deliver a sufficient amount to brain tissue after oral administration. Collectively, these results strongly support the hybridization approach as an efficient strategy to help identify novel scaffolds with a desired pharmacology, and strongly encourage further optimization of 7 to develop more potent neuroprotectants for AD.

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid – DBMA hybrids (1–13) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer’s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), β-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (σ₁R/σ₂R). After a funnel-type screening, 6,7-dimethoxychromone – DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and σ₁R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration.