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Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors

1
School of Biological Science and Technology, University of Jinan, Jinan 250022, China
2
School of Biological Sciences, University of Brasília, Brasília 72220-275, Brazil
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2018, 16(9), 293; https://doi.org/10.3390/md16090293
Received: 14 July 2018 / Revised: 13 August 2018 / Accepted: 18 August 2018 / Published: 21 August 2018
A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development. View Full-Text
Keywords: pulmonarin B; brominated-phenylacetic acid/tacrine hybrids; acetylcholinesterase; butylcholinesterase; anti-amyloid aggregation; Alzheimer’s disease pulmonarin B; brominated-phenylacetic acid/tacrine hybrids; acetylcholinesterase; butylcholinesterase; anti-amyloid aggregation; Alzheimer’s disease
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MDPI and ACS Style

Cheng, Z.-Q.; Song, J.-L.; Zhu, K.; Zhang, J.; Jiang, C.-S.; Zhang, H. Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors. Mar. Drugs 2018, 16, 293.

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