Synthesis of Isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols and N-alkyl Isatins for Inhibition of Butyrylcholinesterase

Abstract:

Alzheimer’s disease (AD) affects over 6.2 million Americans, which has almost doubled from 2000, pushing the disease to be the sixth leading cause of death in the United States. There is an interest in identifying new inhibitors for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to treat or increase understanding of AD. Previous research in our lab on a series of novel isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols (IT2Ts) showed these molecules were moderate to weak inhibitors of AChE. However, further investigation has shown a better potential inhibition of BChE, with the octamethylene-linked molecule having a BChE IC50 of 490 nM. Currently, longer length molecules in this series are being prepared, and enzymatic inhibition results will be presented. Additionally, N-butyl isatin has been shown to have weak BChE inhibition by itself. The synthesis and enzymatic inhibition of additional N-alkyl isatins and indoles will also be presented along with results of AChE and BChE inhibition testing. Molecular modeling will be used to rationalize the enzymatic assay results and visualize interactions between inhibitors and enzymes.