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19 pages, 1286 KB

Open AccessArticle

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

by Barbora Svobodova, Eva Mezeiova, Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Tereza Kobrlova, Daniel Jun, Ondrej Soukup, María Luisa Jimeno, José Marco-Contelles and Jan Korabecny

Biomolecules 2019, 9(8), 379; https://doi.org/10.3390/biom9080379 - 19 Aug 2019

Cited by 32 | Viewed by 6680

Abstract

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes. Full article

(This article belongs to the Special Issue Advances in Cholinesterases)

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19 pages, 2402 KB

Open AccessArticle

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

by Eva Mezeiova, Jan Korabecny, Vendula Sepsova, Martina Hrabinova, Petr Jost, Lubica Muckova, Tomas Kucera, Rafael Dolezal, Jan Misik, Katarina Spilovska, Ngoc Lam Pham, Lucia Pokrievkova, Jaroslav Roh, Daniel Jun, Ondrej Soukup, Daniel Kaping and Kamil Kuca

Molecules 2017, 22(8), 1265; https://doi.org/10.3390/molecules22081265 - 28 Jul 2017

Cited by 28 | Viewed by 8507

Abstract

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. Full article

(This article belongs to the Special Issue The Cholinesterases—Structure, Mechanism, Function and Drug Design: The 25th Anniversary of the Solution of the Crystal Structure of Acetylcholinesterase by Joel L. Sussman and Israel Silman)

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18 pages, 2739 KB

Open AccessArticle

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

by Jan Korabecny, Martin Andrs, Eugenie Nepovimova, Rafael Dolezal, Katerina Babkova, Anna Horova, David Malinak, Eva Mezeiova, Lukas Gorecki, Vendula Sepsova, Martina Hrabinova, Ondrej Soukup, Daniel Jun and Kamil Kuca

Molecules 2015, 20(12), 22084-22101; https://doi.org/10.3390/molecules201219836 - 10 Dec 2015

Cited by 48 | Viewed by 8693

Abstract

Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies. Full article

(This article belongs to the Section Medicinal Chemistry)

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22 pages, 510 KB

Open AccessArticle

7-Methoxytacrine-Adamantylamine Heterodimers as Cholinesterase Inhibitors in Alzheimer’s Disease Treatment — Synthesis, Biological Evaluation and Molecular Modeling Studies

by Katarina Spilovska, Jan Korabecny, Jan Kral, Anna Horova, Kamil Musilek, Ondrej Soukup, Lucie Drtinova, Zuzana Gazova, Katarina Siposova and Kamil Kuca

Molecules 2013, 18(2), 2397-2418; https://doi.org/10.3390/molecules18022397 - 20 Feb 2013

Cited by 76 | Viewed by 11038

Abstract

A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2–8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs. Full article

(This article belongs to the Section Medicinal Chemistry)

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