Kiec-Kononowicz K

References (12)

Title : Multitargeting Histamine H(3) Receptor Ligands among Acetyl- and Propionyl-Phenoxyalkyl Derivatives - Lazewska_2023_Molecules_28_
Author(s) : Lazewska D , Kaleta M , Zareba P , Godyn J , Dubiel M , Honkisz-Orzechowska E , Doroz-Plonka A , Wieckowska A , Stark H , Kiec-Kononowicz K
Ref : Molecules , 28 : , 2023
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder, for which there is no effective cure. Current drugs only slow down the course of the disease, and, therefore, there is an urgent need to find effective therapies that not only treat, but also prevent it. Acetylcholinesterase inhibitors (AChEIs), among others, have been used for years to treat AD. Histamine H(3) receptors (H(3)Rs) antagonists/inverse agonists are indicated for CNS diseases. Combining AChEIs with H(3)R antagonism in one structure could bring a beneficial therapeutic effect. The aim of this study was to find new multitargetting ligands. Thus, continuing our previous research, acetyl- and propionyl-phenoxy-pentyl(-hexyl) derivatives were designed. These compounds were tested for their affinity to human H(3)Rs, as well as their ability to inhibit cholinesterases (acetyl- and butyrylcholinesterases) and, additionally, human monoamine oxidase B (MAO B). Furthermore, for the selected active compounds, their toxicity towards HepG2 or SH-SY5Y cells was evaluated. The results showed that compounds 16 (1-(4-((5-(azepan-1-yl)pentyl)oxy)phenyl)propan-1-one) and 17 (1-(4-((6-(azepan-1-yl)hexyl)oxy)phenyl)propan-1-one) are the most promising, with a high affinity for human H(3)Rs (K(i): 30 nM and 42 nM, respectively), a good ability to inhibit cholinesterases (16: AChE IC(50) = 3.60 microM, BuChE IC(50) = 0.55 microM; 17: AChE IC(50) = 1.06 microM, BuChE IC(50) = 2.86 microM), and lack of cell toxicity up to 50 microM.
ESTHER : Lazewska_2023_Molecules_28_
PubMedSearch : Lazewska_2023_Molecules_28_
PubMedID: 36903593

Title : Benzophenone Derivatives with Histamine H(3) Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease - Godyn_2022_Molecules_28_
Author(s) : Godyn J , Zareba P , Stary D , Kaleta M , Kuder KJ , Latacz G , Mogilski S , Reiner-Link D , Frank A , Doroz-Plonka A , Olejarz-Maciej A , Sudol-Talaj S , Nolte T , Handzlik J , Stark H , Wieckowska A , Malawska B , Kiec-Kononowicz K , Lazewska D , Bajda M
Ref : Molecules , 28 : , 2022
Abstract : The multitarget-directed ligands demonstrating affinity to histamine H(3) receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H(3)R (K(i) = 8 nM) and significant inhibitory activity toward BuChE (IC(50) = 172 nM and 1.16 microM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (P(e)) of 6.3 x 10(-6) cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED(50) = 20.9 mg/kg) and inflammatory (ED(50) = 17.5 mg/kg) pain.
ESTHER : Godyn_2022_Molecules_28_
PubMedSearch : Godyn_2022_Molecules_28_
PubMedID: 36615435

Title : Cyanobiphenyls: Novel H(3) receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease - Godyn_2021_Bioorg.Chem_114_105129
Author(s) : Godyn J , Zareba P , aewska D , Stary D , Reiner-Link D , Frank A , Latacz G , Mogilski S , Kaleta M , Doroz-Plonka A , Lubelska A , Honkisz-Orzechowska E , Olejarz-Maciej A , Handzlik J , Stark H , Kiec-Kononowicz K , Malawska B , Bajda M
Ref : Bioorg Chem , 114 :105129 , 2021
Abstract : Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of K(i) values) for human histamine H(3) receptors (hH(3)R) and good nonselective inhibitory potency (micromolar range of IC(50) values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH(3)R/eeAChE/eqBuChE/hMAO B ligand (5: hH(3)R K(i) = 9.2 nM; eeAChE IC(50) = 2.63 microM; eqBuChE IC(50) = 1.30 microM; hMAO B IC(50) = 0.60 microM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
ESTHER : Godyn_2021_Bioorg.Chem_114_105129
PubMedSearch : Godyn_2021_Bioorg.Chem_114_105129
PubMedID: 34217977

Title : Biphenylalkoxyamine Derivatives-Histamine H(3) Receptor Ligands with Butyrylcholinesterase Inhibitory Activity - Lazewska_2021_Molecules_26_
Author(s) : Lazewska D , Zareba P , Godyn J , Doroz-Plonka A , Frank A , Reiner-Link D , Bajda M , Stary D , Mogilski S , Olejarz-Maciej A , Kaleta M , Stark H , Malawska B , Kiec-Kononowicz K
Ref : Molecules , 26 : , 2021
Abstract : Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H(3) receptors (H(3)Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H(3)R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H(3)R ligands. Most of these compounds show high affinity for human H(3)R (K(i) < 150 nM) and submicromolar inhibition of BuChE (IC(50) < 1 microM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H(3)R, with a K(i) value of 33.9 nM, and for equine serum BuChE, with an IC(50) of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC(50) of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
ESTHER : Lazewska_2021_Molecules_26_
PubMedSearch : Lazewska_2021_Molecules_26_
PubMedID: 34208297

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 : Simultaneous Blockade of Histamine H(3) Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf\/J Mouse Model of Autism - Eissa_2020_Biomolecules_10_
Author(s) : Eissa N , Jayaprakash P , Stark H , Lazewska D , Kiec-Kononowicz K , Sadek B
Ref : Biomolecules , 10 : , 2020
Abstract : Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H(3)R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H(3)R agonist (R)-alpha-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed.
ESTHER : Eissa_2020_Biomolecules_10_
PubMedSearch : Eissa_2020_Biomolecules_10_
PubMedID: 32872194

Title : The Dual-Active Histamine H3 Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice - Eissa_2020_Int.J.Mol.Sci_21_
Author(s) : Eissa N , Azimullah S , Jayaprakash P , Jayaraj RL , Reiner D , Ojha SK , Beiram R , Stark H , Lazewska D , Kiec-Kononowicz K , Sadek B
Ref : Int J Mol Sci , 21 : , 2020
Abstract : The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: Ki = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC50 = 2 microM and EqBuChE: IC50 = 2 microM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.
ESTHER : Eissa_2020_Int.J.Mol.Sci_21_
PubMedSearch : Eissa_2020_Int.J.Mol.Sci_21_
PubMedID: 32503208

Title : Search for new multi-target compounds against Alzheimer's disease among histamine H3 receptor ligands - Bajda_2019_Eur.J.Med.Chem_185_111785
Author(s) : Bajda M , Lazewska D , Godyn J , Zareba P , Kuder K , Hagenow S , Latka K , Stawarska E , Stark H , Kiec-Kononowicz K , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 185 :111785 , 2019
Abstract : Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H3R and both enzymes. Two derivatives were chosen - 5 (IC50=0.46muM (AChE); 0.44muM (BuChE); Ki=159.8nM(H3R)) and 17 (IC50=0.50muM (AChE); 0.76muM (BuChE); Ki=228.2nM(H3R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.
ESTHER : Bajda_2019_Eur.J.Med.Chem_185_111785
PubMedSearch : Bajda_2019_Eur.J.Med.Chem_185_111785
PubMedID: 31669851

Title : The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammation in sodium valproate induced autism in mice - Eissa_2019_Chem.Biol.Interact__108775
Author(s) : Eissa N , Azimullah S , Jayaprakash P , Jayaraj RL , Reiner D , Ojha SK , Beiram R , Stark H , Lazewska D , Kiec-Kononowicz K , Sadek B
Ref : Chemico-Biological Interactions , :108775 , 2019
Abstract : Postnatal exposure to valproic acid (VPA) in rodents induces autism-like neurobehavioral defects which are comparable to the motor and cognitive deficits observed in humans with autism spectrum disorder (ASD). Histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in several cognitive disorders such as Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with ASD. Therefore, the present study aimed at evaluating effect of the novel dual-active ligand E100 with high H3R antagonist affinity and balanced AChE inhibition on autistic-like repetitive behavior, anxiety parameters, locomotor activity, and neuroinflammation in a mouse model of VPA-induced ASD in C57BL/6 mice. E100 (5, 10, and 15mg/kg) dose-dependently and significantly ameliorated repetitive and compulsive behaviors by reducing the increased percentages of nestlets shredded (all P<0.05). Moreover, pretreatment with E100 (10 and 15mg/kg) attenuated disturbed anxiety levels (P<0.05) but failed to restore the hyperactivity observed in the elevated open field test. Furthermore, pretreatment with E100 (10mg/kg) mitigated the increase in the levels of proinflammatory cytokines and expression of NF-kappaB, iNOS, and COX-2 in the cerebellum as well as the hippocampus (all P<0.05). These results demonstrate the ameliorative effects of E100 on repetitive compulsive behaviors in a mouse model of ASD. To our knowledge, this is the first in vivo demonstration of the effectiveness of a potent dual-active H3R antagonist and AChE inhibitor against autistic-like repetitive compulsive behaviors and neuroinflammation, and provides evidence for the role of such compounds in treating ASD.
ESTHER : Eissa_2019_Chem.Biol.Interact__108775
PubMedSearch : Eissa_2019_Chem.Biol.Interact__108775
PubMedID: 31369746

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 : Cholinesterase inhibitory activity of chlorophenoxy derivatives-Histamine H3 receptor ligands - Lazewska_2016_Bioorg.Med.Chem.Lett_26_4140
Author(s) : Lazewska D , Jonczyk J , Bajda M , Szalaj N , Wieckowska A , Panek D , Moore C , Kuder K , Malawska B , Kiec-Kononowicz K
Ref : Bioorganic & Medicinal Chemistry Lett , 26 :4140 , 2016
Abstract : In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range. The most potent in this group was 1-(7-(4-chlorophenoxy)heptyl)homopiperidine (18) inhibiting the both enzymes (EeAChE IC50=1.93muM and EqBuChE IC50=1.64muM). Molecular modeling studies were performed to explain the binding mode of 18 with histamine H3 receptor as well as with cholinesterases.
ESTHER : Lazewska_2016_Bioorg.Med.Chem.Lett_26_4140
PubMedSearch : Lazewska_2016_Bioorg.Med.Chem.Lett_26_4140
PubMedID: 27445168