Hybrids of oxoisoaporphine-tacrine congeners: novel acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation inhibitors.

State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, PR China.
European Journal of Medicinal Chemistry (Impact Factor: 3.43). 08/2011; 46(10):4970-9. DOI: 10.1016/j.ejmech.2011.08.002
Source: PubMed

ABSTRACT A series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation. The new hybrids consist of a unit of 1-azabenzanthrone and a tacrine or its congener, connected through an oligomethylene linker containing an amine group at variable position. These hybrids exhibit high AChE inhibitory activity with IC(50) values in the nanomolar range in most cases. Moreover, five out of the 12 hybrids of this series, particularly those bearing a tetrahydroacridine moiety, exhibit a significant in vitro inhibitory activity toward the AChE-induced and self-induced Aβ aggregation, which makes them promising anti-Alzheimer drug candidates.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.
    Bioorganic & Medicinal Chemistry 09/2014; · 2.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of novel symmetric S,S′-2,2′-(ethane-1,2-diylbis(azanediyl)) bis(2-oxoethane-2,1-diyl) O,O,O′,O′-tetraethyl diphosphorodithioate derivatives (12) was designed and synthesized based on the cluster effect and the multiple binding sites of acetylcholinesterase (AChE). The structures of all the newly synthesized title compounds were characterized by 1H and 13C NMR as well as elemental analyses. Their inhibitory activities against AChE were tested, and compound 12b exhibited the best activity (6.60-fold higher than ethion). The results suggested that the compound would bind to the catalytic center and the narrow gorge of the AChE simultaneously.Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional table.
    Phosphorus Sulfur and Silicon and the Related Elements 08/2013; 188(8). · 0.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Four oxoisoaporphine-lipoic acid hybrids were designed, synthesized, and investigated in this study. To develop the hybrids, the oxoisoaporphine fragment was used for its inhibition of cholinesterases and β-amyloid (Aβ) aggregation, while the unit of lipoic acid was used for its radical-capturing and neuroprotective effects. The hybrids exhibited moderate inhibitory effects on the activity of acetylcholinesterase (AChE), with IC50 values in the micromolar range and low toxicity in SH-SY5Y cells. Moreover, the learning and memory abilities, climbing capability, and average life expectancy of the Aβ42 transgenic Drosophila were all significantly improved by the hybrids. They also enhanced the intracephalic antioxidant activity, the metabolism, and the activity cholinesterase in the flies. More strikingly, Aβ42 aggregation in the hybrids-treated Drosophila was attenuated with effective neuroprotection. Our results indicate the potential of using these oxoisoaporphine-lipoic acid hybrids in AD treatments.
    Chemico-Biological Interactions 09/2014; · 2.98 Impact Factor