Siwek A

References (9)

Title : Serotonin 5-HT(6) Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity-Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer's Disease - Wieckowski_2022_Int.J.Mol.Sci_23_9443
Author(s) : Wieckowski K , Szalaj N , Gryzlo B , Wichur T , Goral I , Slugocka E , Sniecikowska J , Latacz G , Siwek A , Godyn J , Bucki A , Kolaczkowski M , Wieckowska A
Ref : Int J Mol Sci , 23 : , 2022
Abstract : Neurodegeneration leading to Alzheimer's disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT(6) receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman's assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT(6) receptor ligand (K(i) = 22 nM) and human BuChE inhibitor (IC(50) = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals by 35% (150 microM). The study also revealed additional metal-chelating properties of compounds 15 and 18. The presented compounds modulating Alzheimer's disease-related processes might be further developed as multifunctional ligands against the disease.
ESTHER : Wieckowski_2022_Int.J.Mol.Sci_23_9443
PubMedSearch : Wieckowski_2022_Int.J.Mol.Sci_23_9443
PubMedID: 36012707

Title : Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT(6) receptor with anti-aggregation properties against amyloid-beta and tau - Wichur_2021_Eur.J.Med.Chem_225_113783
Author(s) : Wichur T , Pasieka A , Godyn J , Panek D , Goral I , Latacz G , Honkisz-Orzechowska E , Bucki A , Siwek A , Gluch-Lutwin M , Knez D , Brazzolotto X , Gobec S , Kolaczkowski M , Sabate R , Malawska B , Wieckowska A
Ref : Eur Journal of Medicinal Chemistry , 225 :113783 , 2021
Abstract : Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT(6)R antagonists (K(i) = 13 nM and K(i) = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC(50) = 8 nM and IC(50) = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC(50) = 455 nM). Both compounds inhibit aggregation of amyloid beta in vitro (75% for compound 17 and 68% for 35 at 10 microM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 microM and lack of toxicity on HepG2 cell line (IC(50) values of 80 and 21 microM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.
ESTHER : Wichur_2021_Eur.J.Med.Chem_225_113783
PubMedSearch : Wichur_2021_Eur.J.Med.Chem_225_113783
PubMedID: 34461507

Title : Potential of nafimidone derivatives against co-morbidities of epilepsy: In vitro, in vivo, and in silico investigations - Sari_2021_Drug.Dev.Res__
Author(s) : Sari S , Barut B , Marcinkowska M , Sabuncuoglu S , Avci A , Kocak Aslan E , Ozel A , Siwek A
Ref : Drug Dev Res , : , 2021
Abstract : Nafimidone is known for its clinical antiepileptic effects and alcohol derivatives of nafimidone were reported be potent anticonvulsants. These compounds are structurally similar to miconazole, which is known to inhibit cholinesterases, protect neurons, and ameliorate cognitive decline. Herein, we aimed to reveal the potential of three nafimidone alcohol esters (5 g, 5i, and 5 k), which were previously reported for their anticonvulsant effects, against co-morbidities of epilepsy such as inflammatory and neuropathic pain, cognitive and behavioral deficits, and neuron death, and understand their roles in related pathways such as gamma-butyric acid type A (GABA(A) ) receptor and cholinesterases using in vitro, in vivo and in silico methods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used for cytotoxicity evaluation, hippocampal slice culture assay for neuroprotection, formalin test for acute and inflammatory pain, sciatic ligation for neuropathic pain, Morris water maze and open field locomotor tasks for cognitive and behavioral deficits, radioligand binding for GABA(A) receptor affinity, spectrophotometric methods for cholinesterase inhibition in vitro, and molecular docking in silico. The compounds were non-toxic to fibroblast cells. 5 k was neuroprotective against kainic acid-induced neuron death. 5i reduced pain response of mice in both the acute and the inflammatory phases. 5i improved survival upon status epilepticus. The compounds showed no affinity to GABA(A) receptor but inhibited acetylcholinesterase, 5 k also inhibited butyrylcholinesterase. The compounds were predicted to interact mainly with the peripheric anionic site of cholinesterase enzymes. The title compounds showed neuroprotective, analgesic, and cholinesterase inhibitory effects, thus they bear promise against certain co-morbidities of epilepsy with neurological insults.
ESTHER : Sari_2021_Drug.Dev.Res__
PubMedSearch : Sari_2021_Drug.Dev.Res__
PubMedID: 34291476

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 : Rational design of new multitarget histamine H(3) receptor ligands as potential candidates for treatment of Alzheimer's disease - Lazewska_2020_Eur.J.Med.Chem_207_112743
Author(s) : Lazewska D , Bajda M , Kaleta M , Zareba P , Doroz-Plonka A , Siwek A , Alachkar A , Mogilski S , Saad A , Kuder K , Olejarz-Maciej A , Godyn J , Stary D , Sudol S , Wiecek M , Latacz G , Walczak M , Handzlik J , Sadek B , Malawska B , Kiec-Kononowicz K
Ref : Eur Journal of Medicinal Chemistry , 207 :112743 , 2020
Abstract : Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H(3) receptor (H(3)R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H(3)R (hH(3)R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH(3)R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC(50) values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH(3)R (K(i) = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC(50) = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC(50) = 880 nM and 394 nM respectively) and hMAO B (IC(50) = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH(3)R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.
ESTHER : Lazewska_2020_Eur.J.Med.Chem_207_112743
PubMedSearch : Lazewska_2020_Eur.J.Med.Chem_207_112743
PubMedID: 32882609

Title : Anti-Alzheimer's multitarget-directed ligands with serotonin 5-HT6 antagonist, butyrylcholinesterase inhibitory, and antioxidant activity - Marcinkowska_2019_Arch.Pharm.(Weinheim)__e1900041
Author(s) : Marcinkowska M , Bucki A , Panek D , Siwek A , Fajkis N , Bednarski M , Zygmunt M , Godyn J , Del Rio Valdivieso A , Kotanska M , Kolaczkowski M , Wieckowska A
Ref : Arch Pharm (Weinheim) , :e1900041 , 2019
Abstract : Serotonin 5-HT6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT 6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT 6 antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT 6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT 6 receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K i and K b values against 5-HT 6 receptors of 41.8 and 74 nM, respectively, an IC 50 value of 5 microM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.
ESTHER : Marcinkowska_2019_Arch.Pharm.(Weinheim)__e1900041
PubMedSearch : Marcinkowska_2019_Arch.Pharm.(Weinheim)__e1900041
PubMedID: 31162703

Title : New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H3 Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition - Malek_2019_J.Med.Chem_62_11416
Author(s) : Malek R , Arribas RL , Palomino-Antolin A , Totoson P , Demougeot C , Kobrlova T , Soukup O , Iriepa I , Moraleda I , Diez-Iriepa D , Godyn J , Panek D , Malawska B , Gluch-Lutwin M , Mordyl B , Siwek A , Chabchoub F , Marco-Contelles J , Kiec-Kononowicz K , Egea J , de los Rios C , Ismaili L
Ref : Journal of Medicinal Chemistry , 62 :11416 , 2019
Abstract : New tritarget small molecules combining Ca(2+) channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca(2+) channels blockade activity (IC50 = 21 +/- 1 muM), potent affinity against hH3R (Ki = 565 +/- 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 +/- 0.10 muM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
ESTHER : Malek_2019_J.Med.Chem_62_11416
PubMedSearch : Malek_2019_J.Med.Chem_62_11416
PubMedID: 31724859

Title : Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease - Wieckowska_2018_ACS.Chem.Neurosci_9_1195
Author(s) : Wieckowska A , Wichur T , Godyn J , Bucki A , Marcinkowska M , Siwek A , Wieckowski K , Zareba P , Knez D , Gluch-Lutwin M , Kazek G , Latacz G , Mika K , Kolaczkowski M , Korabecny J , Soukup O , Benkova M , Kiec-Kononowicz K , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1195 , 2018
Abstract : Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 muM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
ESTHER : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedSearch : Wieckowska_2018_ACS.Chem.Neurosci_9_1195
PubMedID: 29384656

Title : Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation - Wieckowska_2016_Eur.J.Med.Chem_124_63
Author(s) : Wieckowska A , Kolaczkowski M , Bucki A , Godyn J , Marcinkowska M , Wieckowski K , Zareba P , Siwek A , Kazek G , Gluch-Lutwin M , Mierzejewski P , Bienkowski P , Sienkiewicz-Jarosz H , Knez D , Wichur T , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 124 :63 , 2016
Abstract : As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT6 receptor (Kb = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC50hAChE = 12 nM, IC50hBuChE = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.
ESTHER : Wieckowska_2016_Eur.J.Med.Chem_124_63
PubMedSearch : Wieckowska_2016_Eur.J.Med.Chem_124_63
PubMedID: 27560283