Arisugacin A

A computational docking study of a series of de novo structural analogs of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. In direct comparison to the recently reported X-ray single-crystal structure of (+)-territrem B bound hAChE, the modeling suggests that there is a unique conformational preference for the E-ring that is responsible for the superior inhibitory activity of (+)-arisugacin A against hAChE relative to (+)-territrem B, and that substitutions on the E-ring also play an important role in the protein-ligand interaction.

The first convergent total synthesis of (+/-)-arisugacin A was accomplished by stereoselective construction of the arisugacin skeleton via a Knoevenagel-type reaction of an alpha,beta-unsaturated aldehyde with a 4-hydroxy 2-pyrone and stereoselective dihydroxylation followed by deoxygenation.

A computation docking study of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. The model suggests that (+)-arisugacin A is a dual binding site covalent inhibitor of AChE. These findings are examined in the context of Alzheimer's disease-modifying therapeutic design. (+)-Arisugacin A's revealed mode of action is unique, and may serve as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy.