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Open AccessArticle

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

1
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
2
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
3
Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Juan de la Cierva 3, 28006-Madrid, Spain
4
Centro de Química Orgánica “Lora-Tamayo” (CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Biomolecules 2019, 9(8), 379; https://doi.org/10.3390/biom9080379
Received: 2 August 2019 / Revised: 16 August 2019 / Accepted: 17 August 2019 / Published: 19 August 2019
(This article belongs to the Special Issue Advances in Cholinesterases)
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. View Full-Text
Keywords: tacrine; bis(7)-tacrine; 6-chlorotacrine; 7-methoxytacrine; squaramides; Alzheimer’s disease; cholinesterases; in vitro; in silico tacrine; bis(7)-tacrine; 6-chlorotacrine; 7-methoxytacrine; squaramides; Alzheimer’s disease; cholinesterases; in vitro; in silico
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MDPI and ACS Style

Svobodova, B.; Mezeiova, E.; Hepnarova, V.; Hrabinova, M.; Muckova, L.; Kobrlova, T.; Jun, D.; Soukup, O.; Jimeno, M.L.; Marco-Contelles, J.; Korabecny, J. Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors. Biomolecules 2019, 9, 379.

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