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Isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols for inhibition of acetylcholinesterase

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Abstract

A series of novel isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols (IT2Ts) 1a–1g were designed as acetylcholinesterase (AChE) inhibitors capable of interacting with both the catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme simultaneously. The target IT2Ts were prepared through a short synthesis in moderate yield. The most potent inhibitors of this series 1b and 1c (IC50 = 18.2 and 27.5 μM, respectively) outperformed rivastigmine and were comparable to galantamine, both clinically used AChE inhibitors. Furthermore, 1b displayed non-competitive inhibition patterns in kinetic studies, whereas molecular modeling predicted a simultaneous interaction with both the CAS and PAS. In silico methods predicted several promising drug-like characteristics of 1b. Taken together, these results indicate 1b warrants further investigation as a multitarget-directed ligand for AChE inhibition.

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Acknowledgements

This work was supported through Penn State Behrend new faculty start-up funds (T.J.E.), a Penn State Behrend Undergraduate Student 2021 Academic Year Research Grant (S.M.D.), and a Penn State Behrend Undergraduate Student 2021 Summer Research Fellowship (S.M.D.). The Bruker Avance 400 NMR Spectrometer used in this work was made possible by gifts from the Thomas Lord Charitable Trust and The Orris C. Hirtzel and Beatrice Dewey Hirtzel Memorial Foundation. Mass spectrometric analyses were performed at the Penn State Proteomics and Mass Spectrometry Core Facility, University Park, PA, and we thank Dr. Tatiana Laremore for help with HRMS sample preparation and data collection. We thank Jerry Magraw (Penn State Behrend) for assistance with instrumentation and Dr. Michael Justik (Penn State Behrend) for helpful discussions during the preparation of this manuscript.

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Davis, S.M., Eckroat, T.J. Isatin-linked 4,4-dimethyl-5-methylene-4,5-dihydrothiazole-2-thiols for inhibition of acetylcholinesterase. Med Chem Res 30, 2289–2300 (2021). https://doi.org/10.1007/s00044-021-02800-y

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