Design, synthesis and in vitro testing of 7-methoxytacrine-amantadine analogues: a novel cholinesterase inhibitors for the treatment of Alzheimer’s disease

Špilovská, Katarína; Korábečný, Jan; Horova, Anna; Musílek, Kamil; Nepovimová, Eugenie; Drtinová, Lucie; Gažová, Zuzana; Šipošová, Katarína; Doležal, Rafael; Jun, Daniel; Kuča, Kamil

doi:10.1007/s00044-015-1316-x

Cited by 28 publications

(20 citation statements)

References 49 publications

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“…Focused on K1383 (−13.3 kcal/mol; Figure 3 A,B), the ligand revealed a dual binding site pattern of inhibition with the scutellarin moiety protruding out of the cavity gorge and THA moiety stacked in the CAS of the enzyme. Such an orientation of THA scaffold is highly consistent with other recently described THA dual binders like tacrine-tianeptine or 7-methoxytacrine-adamantylamine heterodimers [ 65 , 66 , 67 ]. On contrary, it has to be stated that opposite orientation, i.e., THA lodging within PAS region, can be also found in the literature like in 7-methoxytacrine- p -anisidine, tacrine-Trolox or 7-methoxytacrine-donepezil like compounds [ 68 , 69 , 70 ].…”

Section: Resultssupporting

confidence: 88%

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

et al. 2017

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A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

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Section: Resultssupporting

confidence: 88%

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

et al. 2017

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“…Anthranilic acid 1 was condensed with cyclohexanone 2 to yield chloro acridine 3 38,39 . Treatment of 3 with different diamine led to 4-8, which were condensed with cinnamic acid to result in the target compounds 9-13.…”

Section: Compound Design and Chemistrymentioning

confidence: 99%

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

Chen

Zhu

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“… a Results are expressed as the mean of at least three experiments; b selectivity for h AChE is determined as ratio IC 50 ( h BChE)/IC 50 ( h AChE); c data taken from Ref. [ 45 , 46 , 47 , 48 ]. …”

Section: Figures Scheme and Tablesmentioning

confidence: 99%

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

et al. 2017

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Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer’s disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors—THA and (−)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

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Design, synthesis and in vitro testing of 7-methoxytacrine-amantadine analogues: a novel cholinesterase inhibitors for the treatment of Alzheimer’s disease

Cited by 28 publications

References 49 publications

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

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