Two novel series of isatin-linked heterocycles have been synthesized and evaluated for cholinesterase inhibition. Isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols (IT2Ts), varying in the number of linking methylene units, were designed as acetylcholinesterase (AChE) inhibitors and prepared through a short synthesis in moderate yield. In an Ellman assay, the most potent inhibitors of this series outperformed rivastigmine and were comparable to galantamine, both clinically used AChE inhibitors, in terms of IC<sub>50</sub>. The best inhibitor displayed non-competitive inhibition patterns in kinetic studies, while molecular modeling predicted a simultaneous interaction with both the CAS and PAS. Subsequent studies are focusing on the structure-activity relationship (SAR) of the isatin moiety by varying substituents on the aromatic ring. The SAR of the thiazoline moiety is also being investigated by addition of a bromo substituent and shifts to imidazoline and benzothiazole heterocycles. Additionally, dimeric 3-indolyl-3-hydroxy-2-oxindoles, formed from condensation of indole with methylene-linked isatin dimers, were prepared. This series of molecules shows selective inhibition of butyrylcholinesterase (BChE) with low micromolar IC<sub>50</sub> values. Subsequent studies are exploring the SAR and mode of interaction of these selective compounds with BChE, and additional synthetic and enzymatic inhibition results of these ongoing studies will be presented.

Isatin-linked heterocycles for inhibition of acetylcholinesterase and butyrylcholinesterase

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