In Situ Selection of Lead Compounds by Click Chemistry: Target-Guided Optimization of Acetylcholinesterase Inhibitors

• DOI: 10.1021/ja043031t
• Publication Date: 2005-05-04T04:52:07Z
• Authors: Antoni Krasiński; Zoran Radić; Roman Manetsch; Jessica Raushel; Palmer Taylor; K. Barry Sharpless; Hartmuth C. Kolb
• Keywords: Tacrine; Lead compound; Dissociation constant; Triazole

The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with variety of acetylene reagents that were not previously known interact the enzyme's peripheral binding site. triazole products, formed enzyme, identified HPLC-mass spectrometry analysis crude reaction mixtures. target-guided search was also successful when performed reagent mixtures containing up 10 components. From 23 reagents, enzyme two phenyltetrahydroisoquinoline (PIQ) building blocks combined tacrine within active center gorge form multivalent simultaneously associate and sites. These new are 3 times as potent our previous phenylphenanthridinium-derived compounds, dissociation constants low 33 femtomolar, they most noncovalent AChE known. In addition, compounds lack permanent positive charge aniline groups possess fewer fused aromatic rings. Remarkably, despite high affinity, displayed surprisingly preference one PIQ enantiomer over other.