Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE–ligand interactions by docking calculations and molecular dynamics simulations

Abstract

Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE-compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding.

Design, Synthesis, and Biological Activity Evaluation of New Donepezil-Like Compounds Bearing Thiazole Ring for the Treatment of Alzheimer’s Disease

“…Moreover, there is a hydrogen bond formation between the carbonyl of the 1-indanone and the amine of Phe295. These identified interactions of donepezil were consistent with the data in the literature and the docking procedure was verified via these findings [12,[35][36][37].…”

Design, Synthesis, and Structure–Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer’s Disease

“…The indole of this amino acid creates a π–π interaction with the 1-indanone ring. Furthermore, a hydrogen bond formation is observed between the carbonyl of the 1-indanone and the amine of Phe295 [ 22 , 23 , 24 , 60 , 61 ].…”

“…Chemically, the aromatic groups of the compounds bind to the PAS region, whereas the moieties carrying a basic center interact with the CAS [ 19 , 20 ]. Dual binding inhibitors such as donepezil bind to both sites; therefore, these types of compounds can show a very potent AChE inhibition profile [ 21 , 22 , 23 , 24 ].…”

Changing Paradigm from one Target one Ligand Towards Multi-target Directed Ligand Design for Key Drug Targets of Alzheimer Disease: An Important Role of In Silico Methods in Multi-target Directed Ligands Design

“…4-Aryl-4-oxo-2-aminylbutanamides were evaluated for anticholinesterase activity through docking and molecular dynamics studies. They suggested that AChE selectivity is due to cycloalkylamino moiety, and a hydrogen bond between ligand –NH– group and AChE Tyr 124 –OH has a very important interaction for activity [34]. Many carbamates derivativesdesigned and synthesized chemically have shown better AChE inhibitory activity than the already present rivastigmine.…”