| Alzheimer's disease (AD) is the most common form of dementia among Americans over the age of 65. Our current research in potential therapeutics involves the synthesis of chimeric inhibitors that contain either silicon or nitrogen based connectors. To this end several meta-substituted aryl trifluoromethyl ketone multifunctional inhibitors targeting both the active site and peripheral site of acetylcholinesterase have been synthesized. The compounds have been evaluated as inhibitors of fetal bovine serum acetylcholinesterase (FBAChE), and/or human recombinant AChE catalyzed hydrolyses of acetylthiocholine. A select number have been evaluated in both enzymes for comparison. All compounds tested show time-dependent inhibition with IC50 values ranging from micromolar to sub-nanomolar for inhibition of FBAChE, and nanomolar to sub-nanomolar for the human enzyme variant. For a select number of compounds further kinetic and thermodynamic parameters including K l, kon, koff, and t1/2 were determined. It was found that the Kl value depended on the identity of the peripheral active site targeting moiety, and the length of the spacer chain. |
