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

Abstract

Three thiosemicarbazone derivatives, namely 4-(dimethylamino)benzaldehyde 4,4-dimethylthiosemicarbazone (HL 1 ), 4-(dimethylamino)benzaldehyde thiosemicarbazone (HL 2 ), and 4-(dimethylamino)benzaldehyde 4methylthiosemicarbazone (HL 3 ), have been synthesized and characterized. The three palladium(II) complexes 1−3 were prepared respectively from HL 1 , HL 2 , and HL 3 . 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 HL 3 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-β, reducing the formation of fibrils. HL 1 , HL 3 , 2, and 3 display IC 50 values (i.e., the concentrations required to reduce Aβ fibrillation by 50%) below 1 μM, lower that of the reference compound catechin (IC 50 = 2.8 μM). Finally, in cellulo studies with E. coli cells revealed that the palladium(II) compounds are significantly more efficient than the free ligands in inhibiting Aβ aggregation inside bacterial inclusion bodies, thus illustrating a beneficial effect of metal coordination.

Two Different Thiosemicarbazone Tauto‐Conformers Coordinate to Palladium (II). Stability and Biological Studies of the Final Complexes

“…The calculated values for [Pd(L 1 ) 2 ] and [Pd(L 2 ) 2 ] are 8,4 10 −5 and 4,3 10 −4 s −1 . In comparison with cisplatin constants (k obs ), 1,98 10 −4 s −1 reported at the same conditions, [32] the value for [Pd(L 2 ) 2 ] show better affinity than the value for [Pd(L 1 ) 2 ] with HEWL, being this last lower than cisplatin's one but in the same range.…”

Dual Effect of Prussian Blue Nanoparticles on Aβ40 Aggregation: β-Sheet Fibril Reduction and Copper Dyshomeostasis Regulation

“…Surprisingly, acceleration of aggregation was observed, but a drastic reduction of the amount of β-sheet fibrils was detected in the presence of PBNPs (Figure a and Table ). Notably, in the presence of PBNPs, the elongation ( k e ) process was practically unaltered, whereas the nucleation step ( k n ) increased by about 20-folds; this feature is also reflected in the lag time ( t 0 ), t 1/2 , and t 1 , which are halved (see Table ). The observed ThT-signal reduction corroborates the decrease in the β-sheet content observed by ATR–FTIR (Figure b).…”

Synthesis and Potential Dual Inhibitory Activity Against Acetylcholinesterase and Butyrylcholinesterase of Galactose‐Conjugated Isatin β‐Thiosemicarbazones

“…Additionally, several derivatives of isatin have been synthesized and probed for inhibitory activity of AChE and BChE enzymes, [20] including hydrazones [21] and (thio)semicarbazones. [22] Figure 2 displays some representative isatin derivatives that exhibit the inhibitory activity against AChE and BChE.…”