Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities |
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Authors: | Masashi Shinada Fuminori Narumi Yuji Osada Koji Matsumoto Takayasu Yoshida Kazuhiro Higuchi Tomomi Kawasaki Hiroyuki Tanaka Mitsutoshi Satoh |
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Affiliation: | Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. |
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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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