Design and synthesis of tacrine–ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates

Fang, Lei; Kraus, Birgit; Lehmann, Jochen; Heilmann, Joerg; Zhang, Yihua; Decker, Michael

doi:10.1016/j.bmcl.2008.03.073

Cited by 175 publications

(133 citation statements)

References 24 publications

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“…With regard to the second path, tacrine derivatives 9 were prepared by reacting ethylenediamine or octane-1,8-diamine with 9-chlorotetrahydroacridine 8 using previously described procedures. 8,22 The synthesis of bivalent compounds (11a, b) with two tacrine moieties used a 1:2 ratio of DTE dicarboxylic acid and the tacrine derivative, whereas for the synthesis of univalent compounds (10a, b) a 1:1 ratio was applied (Scheme 1). In each case, two different spacer lengths were incorporated.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Therefore, compound 11b in its ring-opened form represents a noncompetitive inhibitor of AChE. 8,25,26 In contrast, in its ringclosed form, a different Lineweaver−Burk curve illustrates the difference in K m and V max values. The K m values differ with different 11b concentrations, while the V max values remain essentially unchanged; that is, this photoisomer of 11b is a competitive inhibitor of AChE and therefore presumably might only inhibit the CAS of the enzyme.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Chen

Wehle

Kuzmanovic³

et al. 2014

ACS Chem. Neurosci.

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103

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Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl-(AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ 1−40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ringopen and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ringclosed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Chen

Wehle

Kuzmanovic³

et al. 2014

ACS Chem. Neurosci.

Self Cite

100

103

View full text Add to dashboard Cite

show abstract

“…Few of this class of inhibitors have yet been approved for AD therapy (Bachurin, 2003) and most of them have short half-life and peripheral cholinergic side effects (Fang et al, 2008;Mukherjee et al, 2007b;Nordberg & Svensson, 1998;Perry et al, 2003) which significantly limit its therapeutic use. Therefore, natural sources of compounds showing AChE inhibitory capacity must be sought.…”

Section: Research Articlementioning

confidence: 99%

Bioactive compounds from endemic plants of Southwest Portugal: Inhibition of acetylcholinesterase and radical scavenging activities

Tavares¹,

Tyagi²,

Barata³

et al. 2011

Pharmaceutical Biology

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“…Many compounds (e.g. galantamine and tacrine for Alzheimer's disease and acarbose for diabetes mellitus) are synthetically developed in drug industry, but they show adverse effects including gastrointestinal diseases and hepatotoxicity [7][8][9] . In this context, enzyme inhibitory properties of medicinal plants or plant-derived products are of great value in drug development era since their possible uses as natural enzyme inhibitors emerged from growing tendency to replace synthetic inhibitors by natural ones.…”

Section: Introductionmentioning

confidence: 99%

GC-MS analysis and in vitro antioxidant and enzyme inhibitory activities of essential oil from aerial parts of endemic Thymus spathulifolius Hausskn. et Velen

Ceylan

Zengin

Uysal

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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We investigated the antioxidant and enzyme inhibitory activities and chemical composition of the hydro-distilled essential oil (0.35% yield) from aerial parts of Thymus spathulifolius. Antioxidant capacity of the oil was assessed by different methods including free radical scavenging (DPPH and ABTS), reducing power (FRAP and CUPRAC) and phosphomolybdenum assay. Inhibitory activities were analyzed against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), a-amylase, a-glucosidase, and tyrosinase. Twenty-one constituents were identified representing 97.2% of the total oil with thymol (50.5%), borneol (16.7%) and carvacrol (7.7%) as the major components. The essential oil exhibited good antioxidant activity with IC 50 values of 3.82 and 0.22 mg/mL determined by free radical scavenging DPPH and ABTS, respectively. EC 50 values of FRAP and CUPRAC were found to be 0.12 and 0.34 mg/mL, respectively. The results of the present study support the uses of T. spathulifolius essential oil as a source of natural antioxidants and bioactivities for functional foods and phytomedicines.

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Design and synthesis of tacrine–ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates

Cited by 175 publications

References 24 publications

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

Bioactive compounds from endemic plants of Southwest Portugal: Inhibition of acetylcholinesterase and radical scavenging activities

GC-MS analysis and in vitro antioxidant and enzyme inhibitory activities of essential oil from aerial parts of endemic Thymus spathulifolius Hausskn. et Velen

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