NO-donor thiacarbocyanines as multifunctional agents for Alzheimer's disease

Some symmetrical and unsymmetrical thiacarbocyanines bearing NO-donor nitrooxy and furoxan moieties were synthesized and studied as candidate anti-Alzheimer's drugs. All products activated soluble guanylate cyclase (sGC) in a dose-dependent manner, depending on the presence in their structures of NO-donor groups. None displayed toxicity when tested at concentrations below 10μM on human brain microvascular endothelial cells (hCMEC/D3). Some products were capable of inhibiting amyloid β-protein (Aβ) aggregation, with a potency in the low μM concentration range, and of inhibiting aggregation of human recombinant tau protein in amyloid fibrils when incubated with the protein at 1μM concentration. Nitrooxy derivative 21 and furoxan derivative 22 were selected to investigate synaptic plasticity. Both products, tested at 2μM concentration, counteracted the inhibition of long-term potentiation (LTP) induced by Aβ42 in hippocampal brain slices.