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  • Title: Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities.
    Author: Shinada M, Narumi F, Osada Y, Matsumoto K, Yoshida T, Higuchi K, Kawasaki T, Tanaka H, Satoh M.
    Journal: Bioorg Med Chem; 2012 Aug 15; 20(16):4901-14. PubMed ID: 22831800.
    Abstract:
    Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
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