Chalupova K


Full name : Chalupova Katarina

First name : Katarina

Mail : University Hospital Hradec Kralove

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Country : Czech Republic

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References (5)

Title : Huprine Y - tryptophan heterodimers with potential implication to Alzheimer's disease treatment - Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
Author(s) : Mezeiova E , Hrabinova M , Hepnarova V , Jun D , Janockova J , Muckova L , Prchal L , Kristofikova Z , Kucera T , Gorecki L , Chalupova K , Kunes J , Hroudova J , Soukup O , Korabecny J
Ref : Bioorganic & Medicinal Chemistry Lett , :128100 , 2021
Abstract : The search for novel and effective therapeutics for Alzheimer's disease (AD) is the main quest that remains to be resolved. The goal is to find a disease-modifying agent able to confront the multifactorial nature of the disease positively. Herewith, a family of huprineY-tryptophan heterodimers was prepared, resulting in inhibition of cholinesterase and neuronal nitric oxide synthase enzymes, with effect against amyloid-beta (Abeta) and potential ability to cross the blood-brain barrier. Their cholinesterase pattern of behavior was inspected using kinetic analysis in tandem with docking studies. These heterodimers exhibited a promising pharmacological profile with strong implication in AD.
ESTHER : Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
PubMedSearch : Mezeiova_2021_Bioorg.Med.Chem.Lett__128100
PubMedID: 33984470

Title : Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimes drugs dealing with cholinergic, amyloid and mitochondrial systems - Nepovimova_2020_Bioorg.Chem_107_104596
Author(s) : Nepovimova E , Svobodova L , Dolezal R , Hepnarova V , Junova L , Jun D , Korabecny J , Kucera T , Gazova Z , Motykova K , Kubackova J , Bednarikova Z , Janockova J , Jesus C , Cortes L , Pina J , Rostohar D , Serpa C , Soukup O , Aitken L , Hughes RE , Musilek K , Muckova L , Jost P , Chvojkova M , Vales K , Valis M , Chrienova Z , Chalupova K , Kuca K
Ref : Bioorg Chem , 107 :104596 , 2020
Abstract : A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid beta (Abeta) aggregation and mitochondrial enzyme ABAD, whose interaction with Abeta leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Abeta aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC(50) value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 microM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
ESTHER : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedSearch : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedID: 33421953

Title : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE

Title : Donepezil Derivatives Targeting Amyloid-beta Cascade in Alzheimer's Disease - Mezeiova_2019_Curr.Alzheimer.Res_16_772
Author(s) : Mezeiova E , Chalupova K , Nepovimova E , Gorecki L , Prchal L , Malinak D , Kuca K , Soukup O , Korabecny J
Ref : Curr Alzheimer Res , 16 :772 , 2019
Abstract : Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Abeta) peptide. The targeting includes direct interaction of the compounds with Abeta, AChE-induced Abeta aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Abeta assembly.
ESTHER : Mezeiova_2019_Curr.Alzheimer.Res_16_772
PubMedSearch : Mezeiova_2019_Curr.Alzheimer.Res_16_772
PubMedID: 30819078

Title : UHPLC-HRMS study of anti-Alzheimer's drug candidates: metabolism of 7-MEOTA-tryptophan hybrids hampers their passage into brain - Mzik_2019_J.Pharm.Biomed.Anal_174_134
Author(s) : Mzik M , Zdarova-Karasova J , Chalupova K , Korabecny J , Palicka V , Sestak V
Ref : J Pharm Biomed Anal , 174 :134 , 2019
Abstract : Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.
ESTHER : Mzik_2019_J.Pharm.Biomed.Anal_174_134
PubMedSearch : Mzik_2019_J.Pharm.Biomed.Anal_174_134
PubMedID: 31167157