Jukic M


Full name : Jukic Mila

First name : Mila

Mail : Faculty of Chemistry and Technology\; University of Split\; Teslina 10\; HR-21000 Split

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Country : Croatia

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References (9)

Title : Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds - Groselj_2023_Acta.Chim.Slov_70_545
Author(s) : Groselj U , Grsic M , Meden A , Knez D , Jukic M , Svete J , Gobec S
Ref : Acta Chim Slov , 70 :545 , 2023
Abstract : Synthesis and anticholinesterase activity of 18 previously unpublished indole- and tryptophan-derived compounds are disclosed. These sp3-rich compounds containing an indole structural unit exhibit selective submicromolar inhibition of human butyrylcholinesterase (hBChE). The structures of the newly synthesized compounds were confirmed by 1H and 13C NMR, IR spectroscopy, and high-resolution mass spectrometry.
ESTHER : Groselj_2023_Acta.Chim.Slov_70_545
PubMedSearch : Groselj_2023_Acta.Chim.Slov_70_545
PubMedID: 38124635

Title : Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT6R antagonists with beta-amyloid anti-aggregation properties - Wichur_2021_Eur.J.Med.Chem_225_113792
Author(s) : Wichur T , Godyn J , Goral I , Latacz G , Bucki A , Siwek A , Gluch-Lutwin M , Mordyl B , Sniecikowska J , Walczak M , Knez D , Jukic M , Salat K , Gobec S , Kolaczkowski M , Malawska B , Brazzolotto X , Wieckowska A
Ref : Eur Journal of Medicinal Chemistry , 225 :113792 , 2021
Abstract : The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and beta-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Abeta aggregation (53% at 10 microM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
ESTHER : Wichur_2021_Eur.J.Med.Chem_225_113792
PubMedSearch : Wichur_2021_Eur.J.Med.Chem_225_113792
PubMedID: 34530376
Gene_locus related to this paper: human-BCHE

Title : N-alkylpiperidine carbamates as potential anti-Alzheimer's agents - Kosak_2020_Eur.J.Med.Chem_197_112282
Author(s) : Kosak U , Strasek N , Knez N , Jukic M , Zakelj S , Zahirovic A , Pislar A , Brazzolotto X , Nachon F , Kos J , Gobec S , Knez D
Ref : Eur Journal of Medicinal Chemistry , 197 :112282 , 2020
Abstract : Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 muM), BChE (IC50 = 0.56 muM) and MAO-B (IC50 = 26.1 muM) inhibitor 10, dual AChE (IC50 = 2.25 muM) and BChE (IC50 = 0.81 muM) inhibitor 22, selective BChE (IC50 = 0.06 muM) inhibitor 13, and selective MAO-B (IC50 = 0.18 muM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid beta1-42 (Abeta1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Abeta1-42 anti-aggregation effects.
ESTHER : Kosak_2020_Eur.J.Med.Chem_197_112282
PubMedSearch : Kosak_2020_Eur.J.Med.Chem_197_112282
PubMedID: 32380361
Gene_locus related to this paper: human-BCHE

Title : Biological Evaluation of 8-Hydroxyquinolines as Multi-Target Directed Ligands for Treating Alzheimer's Disease - Knez_2019_Curr.Alzheimer.Res_16_801
Author(s) : Knez D , Sosic I , Pislar A , Mitrovic A , Jukic M , Kos J , Gobec S
Ref : Curr Alzheimer Res , 16 :801 , 2019
Abstract : BACKGROUND: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD). OBJECTIVE: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. METHODS: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid beta (Abeta) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Abeta species, and the effects of compound 2 on apoptotic cascade. RESULTS: Compounds 2-4 competitively inhibited cathepsin B beta-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Abeta aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 muM. Compound 2 exerted neuroprotective effects towards Abeta toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Abeta1-42. CONCLUSION: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.
ESTHER : Knez_2019_Curr.Alzheimer.Res_16_801
PubMedSearch : Knez_2019_Curr.Alzheimer.Res_16_801
PubMedID: 31660830

Title : Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease - Meden_2019_Chem.Commun.(Camb)_55_3765
Author(s) : Meden A , Knez D , Jukic M , Brazzolotto X , Grsic M , Pislar A , Zahirovic A , Kos J , Nachon F , Svete J , Gobec S , Groselj U
Ref : Chem Commun (Camb) , 55 :3765 , 2019
Abstract : We have identified tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors. They are defined according to their chemical modularity, novel binding mode revealed by five solved crystal structures with human BChE, low cytotoxicity, and predicted permeability of the blood-brain barrier. Altogether, these factors indicate their potential as unique lead compounds for symptomatic therapy against Alzheimer's disease.
ESTHER : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedSearch : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedID: 30864579
Gene_locus related to this paper: human-BCHE

Title : Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities - Knez_2018_Eur.J.Med.Chem_156_598
Author(s) : Knez D , Coquelle N , Pislar A , Zakelj S , Jukic M , Sova M , Mravljak J , Nachon F , Brazzolotto X , Kos J , Colletier JP , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 156 :598 , 2018
Abstract : The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki=1.09+/-0.12nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu(2+) ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Abeta1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
ESTHER : Knez_2018_Eur.J.Med.Chem_156_598
PubMedSearch : Knez_2018_Eur.J.Med.Chem_156_598
PubMedID: 30031971
Gene_locus related to this paper: human-BCHE

Title : The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity - Kosak_2018_J.Med.Chem_61_119
Author(s) : Kosak U , Brus B , Knez D , Zakelj S , Trontelj J , Pislar A , Sink R , Jukic M , Zivin M , Podkowa A , Nachon F , Brazzolotto X , Stojan J , Kos J , Coquelle N , Salat K , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 61 :119 , 2018
Abstract : The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-pi interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
ESTHER : Kosak_2018_J.Med.Chem_61_119
PubMedSearch : Kosak_2018_J.Med.Chem_61_119
PubMedID: 29227101
Gene_locus related to this paper: human-BCHE

Title : Screening for acetylcholinesterase inhibition and antioxidant activity of selected plants from Croatia - Jukic_2012_Nat.Prod.Res_26_1703
Author(s) : Jukic M , Burcul F , Carev I , Politeo O , Milos M
Ref : Nat Prod Res , 26 :1703 , 2012
Abstract : The methanol, ethyl acetate and chloroform extracts of selected Croatian plants were tested for their acetylcholinesterase (AChE) inhibition and antioxidant activity. Assessment of AChE inhibition was carried out using microplate reader at 1 mg mL(-)(1). Antioxidant capacities were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test and ferric reducing/antioxidant power assay (FRAP). Total phenol content (TPC) of extracts were determined using Folin-Ciocalteu colorimetric method. Out of 48 extracts, only methanolic extract of the Salix alba L. cortex exerted modest activity towards AChE, reaching 50.80% inhibition at concentration of 1 mg mL(-)(1). All the other samples tested had activity below 20%. The same extract performed the best antioxidative activity using DPPH and FRAP method, too. In essence, among all extracts used in the screening, methanolic extracts showed the best antioxidative activity as well as highest TPC.
ESTHER : Jukic_2012_Nat.Prod.Res_26_1703
PubMedSearch : Jukic_2012_Nat.Prod.Res_26_1703
PubMedID: 22008036

Title : In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone - Jukic_2007_Phytother.Res_21_259
Author(s) : Jukic M , Politeo O , Maksimovic M , Milos M
Ref : Phytother Res , 21 :259 , 2007
Abstract : The aim of this study was to examine in vitro the inhibitory activity exerted by the main constituents of essential oil obtained from the aromatic plant Thymus vulgaris L. on acetylcholinesterase (AChE). The total essential oil and selected compounds, specifically linalool and thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone, were tested for AChE inhibition. Thymohydroquinone exhibited the strongest AChE inhibitory effect over the range of concentrations. The AChE inhibitory potential decreased in the following order: thymohydroquinone > carvacrol > thymoquinone > essential oil > thymol > linalool. It is interesting that the AChE inhibitory effect exerted by carvacrol was 10 times stronger than that exerted by its isomer thymol, although thymol and carvacrol have a very similar structure.
ESTHER : Jukic_2007_Phytother.Res_21_259
PubMedSearch : Jukic_2007_Phytother.Res_21_259
PubMedID: 17186491