Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

M S Vishnu; V Pavankumar; Sandeep Kumar; A Senthil Raja

doi:10.1002/cmdc.201900277

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

ChemMedChem. 2019 Jul 17;14(14):1359-1376. doi: 10.1002/cmdc.201900277. Epub 2019 Jul 8.

Authors

M S Vishnu¹, V Pavankumar¹, Sandeep Kumar¹, A Senthil Raja¹

Affiliation

¹ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University) Varanasi, Varanasi, 221005, Uttar Pradesh, India.

PMID: 31177620
DOI: 10.1002/cmdc.201900277

Abstract

A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC₅₀ values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide (3) was identified as a lead AChE inhibitor with IC₅₀ =0.052±0.006 μm. N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide (2) was the lead MAO-B inhibitor with IC₅₀ =0.034±0.007 μm, and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.

Keywords: acetylcholinesterase; hydrazones; molecular docking; monoamine oxidase inhibitors; piperonylic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Benzoates / chemical synthesis
Benzoates / chemistry*
Benzoates / metabolism
Benzoates / pharmacokinetics
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Catalytic Domain
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry*
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / pharmacokinetics
Enzyme Assays
Humans
Hydrazones / chemical synthesis
Hydrazones / chemistry*
Hydrazones / metabolism
Hydrazones / pharmacokinetics
Hydrophobic and Hydrophilic Interactions
Isatin / analogs & derivatives*
Isatin / chemical synthesis
Isatin / metabolism
Isatin / pharmacokinetics
Kinetics
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / chemistry
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry*
Monoamine Oxidase Inhibitors / metabolism
Monoamine Oxidase Inhibitors / pharmacokinetics
Protein Binding
Structure-Activity Relationship

Substances

Benzoates
Cholinesterase Inhibitors
Hydrazones
Monoamine Oxidase Inhibitors
Isatin
Monoamine Oxidase
monoamine oxidase A, human
Acetylcholinesterase
Butyrylcholinesterase
piperonylic acid