N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as β-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation

Najmeh Edraki; Omidreza Firuzi; Yousef Fatahi; Mohammad Mahdavi; Mehdi Asadi; Saeed Emami; Kouros Divsalar; Ramin Miri; Aida Iraji; Mehdi Khoshneviszadeh; Loghman Firoozpour; Abbas Shafiee; Alireza Foroumadi

doi:10.1002/ardp.201400322

N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as β-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation

Arch Pharm (Weinheim). 2015 May;348(5):330-7. doi: 10.1002/ardp.201400322. Epub 2015 Mar 19.

Authors

Najmeh Edraki¹, Omidreza Firuzi, Yousef Fatahi, Mohammad Mahdavi, Mehdi Asadi, Saeed Emami, Kouros Divsalar, Ramin Miri, Aida Iraji, Mehdi Khoshneviszadeh, Loghman Firoozpour, Abbas Shafiee, Alireza Foroumadi

Affiliation

¹ Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

PMID: 25787800
DOI: 10.1002/ardp.201400322

Abstract

A novel series of N-(2-(piperazin-1-yl)phenyl)aryl carboxamide derivatives were simply synthesized by Ugi-multicomponent reaction as β-secretase (BACE1) inhibitors. The BACE1 inhibitory activity of the synthesized compounds was examined using a Forester resonance energy transfer (FRET)-based assay. Among the tested compounds, the N-(5-bromo-2-(4-phenylpiperazine-1-yl)phenyl)thiophene-carboxamide derivative 14 containing the N-cyclohexyl indole acetamide moiety showed superior BACE1 inhibition at 10 and 40 µM. The results of the molecular docking study indicated that compound 14 establishes favorable hydrogen bonding interactions with the catalytic amino acid residues Asp228 and Thr72 and could be well accommodated in the flap region and P2 and P'2 pockets of the BACE1 active site.

Keywords: Alzheimer's disease; BACE1 inhibitors; Docking study; N-Phenylpiperazine; Ugi-multicomponent reaction.

Publication types

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

MeSH terms

Amides / chemical synthesis
Amides / metabolism
Amides / pharmacology*
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / metabolism
Binding Sites
Catalytic Domain
Computer-Aided Design
Drug Design
Fluorescence Resonance Energy Transfer
Hydrogen Bonding
Molecular Docking Simulation
Piperazines / chemical synthesis
Piperazines / metabolism
Piperazines / pharmacology*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / metabolism
Protease Inhibitors / pharmacology*
Protein Conformation
Structure-Activity Relationship

Substances

Amides
Piperazines
Protease Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases