Lipase-catalysed synthesis of new acetylcholinesterase inhibitors : N-benzylpiperidine aminoacid derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 4; pp. 731 - 738
• Main Authors: MARTINEZ, A, LANOT, C, PEREZ, C, CASTRO, A, LOPEZ-SERRANO, P, CONDE, S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.04.2000
• Subjects: Acetylcholinesterase - drug effects; Biological and medical sciences; Candida - enzymology; Catalysis; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Erythrocytes - drug effects; Erythrocytes - enzymology; Humans; Lipase - metabolism; Medical sciences; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Static Electricity; Similarity; Alzheimer disease; Nitrogen heterocycle; Triacylglycerol lipase; Esterases; Acetylcholinesterase; Modeling; Amidation; Aminoester; Structure activity relation; Donepezil; Molecular model; Piperidine derivatives; Anticholinesterase agent; Chemical synthesis; Human; Regioselectivity; Enzyme; Aminoamide; Benzene derivatives; Enzyme inhibitor; In vitro; Carboxylic ester hydrolases; α-Aminoacid; Hydrolases; Carboxamide; Piperazine derivatives; Electrostatic model; Enzymatic reaction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00020-1

New acetylcholinesterase inhibitors were synthetized via a lipase-mediated regioselective amidation using Candida antarctica lipase B as a biocatalyst in the key step. The new compounds have two different structural fragments: a N-benzylpiperidine moiety to anchor the enzyme active site and a dicarboxylic aminoacid to act as a biological carrier. Some analogues of N-benzylpiperazine were also synthesised and studied but they did not display AChE inhibitor activity. A preliminary structure activity relationship study was performed employing some computational techniques as similarity indices and electrostatic potential maps.