Thiosemicarbazone Derivatives as Inhibitors of Amyloid-β Aggregation: Effect of Metal Coordination

Three thiosemicarbazone derivatives, namely 4-(dimethylamino)-benzaldehyde 4,4-dimethylthiosemicarbazone (HL1), 4-(dimethylamino)-benzaldehyde thiosemicarbazone (HL2), and 4-(dimethylamino)-benzaldehyde 4-methylthiosemicarbazone (HL), have been synthesized and characterized. The three palladium(II) complexes 1-3 were prepared respectively from HL1, HL2, and HL3. The crystal structures of two coordination compounds, namely Pd(L-2)(2) (2) and Pd(L-3)(2) (3), were obtained, which showed the expected square-planar environment for the metal centers. The ligand HL3 and the Pd(II) complexes 1-3, which are stable in buffered solutions containing up to 5% DMSO, exhibit remarkable inhibitory properties against the aggregation of amyloid-beta, reducing the formation of fibrils. HL1, HL3, 2, and 3 display IC50 values (i.e., the concentrations required to reduce A beta fibrillation by 50%) below 1 mu M, lower that of the reference compound catechin (IC50 = 2.8 mu W). Finally, in cellulo studies with E. coli cells revealed that the palladium(II) compounds are significantly more efficient than the free ligands in inhibiting aggregation inside bacterial inclusion bodies, thus illustrating a beneficial effect of metal coordination.