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

Abstract

AbstractA series of different isatin‐thiosemicarbazones 4 a–4 t derived from corresponding substituted isatins and N‐(2,3,4,6‐tetra‐O‐acetyl‐β‐d‐galactopyranosyl)thiosemicarbazide had been synthesized. Their anti‐Alzheimer activity were studied through the inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of these compounds exhibited inhibitory activities against these enzymes. Of these isatin N‐(2,3,4,6‐tetra‐O‐acetyl‐β‐d‐galactoranosyl)thiosemicarbazones 4 a–4 t, in IC50 range below 0.05 μM, some thiosemicarbazones exhibited potent inhibitory activity against AChE enzyme, including 4 s (1‐benzyl)>4 t (1‐phenthyl)>4 p (1‐allyl)>4 r (1‐t‐butyl), and others exhibited potent inhibitory activity against BChE, including 4 t (1‐phenthyl)>4 o (1‐propyl)>4 q (1‐butyl)> 4 s (1‐benzyl). Enzymic kinetics of AChE and BChE inhibition of 4 s and 4 t, were studied. These compounds with strong inhibitory activity had been further investigated in induced fit docking studies as well as molecular dynamics simulations. The obtained resulting simulations indicate that strong ligand‐residues interactions were decisive factors to inhibitory activity of 4 s and 4 t against AChE and BChE enzymes, respectively.