Modular Mimics of Neuroactive Alkaloids – Design, Synthesis, and Cholinesterase Inhibitory Activity of Novel Rivastigmine Analogs

Erika Yu, Shloka Raghavan, Harrison Xu, Tvisha Nepani, Niharika Nambiar, Anushka Peer, Alice Finkelstein, and Edward Njoo

Aspiring Scholars Research Directed Program


For centuries, neuroactive alkaloids isolated from naturally occurring phytochemical sources have been crucial in the identification and optimization of small molecules with potency in treating neurological disorders. While some of these compounds have gone on to clinical use themselves, others have inspired the development of synthetic analogs, which might possess greater potency or better pharmacological features than the natural product itself. One such naturally occurring alkaloid, physostigmine, which is found in the calabar bean plant Physostigma venenosum, has been demonstrated to be a potent cholinesterase inhibitor. However, some of physostigmine’s characteristics limit its therapeutic potential, prompting the development of its synthetic counterpart, rivastigmine. The research in our group focused on the synthetic optimization of rivastigmine and its analogs, utilizing computer modeling and biological assays to determine the most favorable analog for inhibition of acetylcholinesterase (AChE). Through such studies, it was determined that rivastigmine and its analogs were less effective at inhibiting AChE than physostigmine. This discovery prompted us to pursue two routes: the synthesis of S-enantiopure versions of our analogs with the goal of making more potent analogs and the study of biological activity for all analogs on both cholinesterase enzymes to determine enzyme selectivity.

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