Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

• Published in: Bioorganic & medicinal chemistry letters 2012-08, Vol.22 (15), p.4926-4929
• Main Authors: Lewellyn, Kevin, Bialonska, Dobroslawa, Chaurasiya, Narayan D., Tekwani, Babu L., Zjawiony, Jordan K.
• Format: Article
• Language: English
• Subjects: Aplysinopsin analogs; Biological and medical sciences; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Humans; Indole alkaloids; Medical sciences; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine oxidase inhibitors; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - metabolism; Natural product; Neurotransmitters; Pharmacology. Drug treatments; Protein Binding - drug effects; Structure-Activity Relationship; Tryptophan - analogs & derivatives; Tryptophan - chemical synthesis; Tryptophan - chemistry; Tryptophan - metabolism; Tryptophan - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.058

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC50 of 5.6nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2′, and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.