title: N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as β-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation.
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.
authors: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Najmeh
authors: N
authors: Edraki
authors: Omidreza
authors: O
authors: Firuzi
authors: Yousef
authors: Y
authors: Fatahi
authors: Mohammad
authors: M
authors: Mahdavi
authors: Mehdi
authors: M
authors: Asadi
authors: Saeed
authors: S
authors: Emami
authors: Kouros
authors: K
authors: Divsalar
authors: Ramin
authors: R
authors: Miri
authors: Aida
authors: A
authors: Iraji
authors: Mehdi
authors: M
authors: Khoshneviszadeh
authors: Loghman
authors: L
authors: Firoozpour
authors: Abbas
authors: A
authors: Shafiee
authors: Alireza
authors: A
authors: Foroumadi
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D017076:Computer-Aided Design; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D010879:Piperazines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases
keywords: Alzheimer's disease; BACE1 inhibitors; Docking study; N-Phenylpiperazine; Ugi-multicomponent reaction