Background: Hydrazide-hydrazones have been known as scaffold with various biological
activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors
are mainstays of dementias’ treatment.
Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential
central AChE and BuChE inhibitors.
Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4-
hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit
AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also
physicochemical and structural parameters for CNS delivery.
Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5
and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a
balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4-
nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most
potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established,
and molecular docking studies confirmed interaction with enzymes.
Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against
AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia.
They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg
approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.