Jonczyk J


Full name : Jonczyk Jakub

First name : Jakub

Mail : Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Cracow, Medyczna 9

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Country : Poland

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References (23)

Title : New cyclopentaquinoline and 3,5-dichlorobenzoic acid hybrids with neuroprotection against oxidative stress for the treatment of Alzheimer's disease - Czarnecka_2023_J.Enzyme.Inhib.Med.Chem_38_2158822
Author(s) : Czarnecka K , Girek M , Krecisz P , Skibinski R , Latka K , Jonczyk J , Bajda M , Szymczyk P , Galita G , Kabzinski J , Majsterek I , Espargaro A , Sabate R , Szymanski P
Ref : J Enzyme Inhib Med Chem , 38 :2158822 , 2023
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial disease. The present study evaluates eight derivatives (3a-3h) as candidates with stronger anti-AD potential but with less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve in the neurodegeneration. The neuroprotective properties of 3e against oxidative stress were done in three experiments using MTT test. The anti-AD potential was determined based on their anticholinesterase inhibition ability, determined using Ellman's method, Abeta aggregation potential according to thioflavin (Th) fluorescence assay, and their antioxidative and anti-inflammatory activities. Compound 3e exhibited moderate cholinesterase inhibition activity (AChE, IC(50) = 0.131 microM; BuChE, IC(50) = 0.116 microM; SI = 1.13), significant inhibition of Abeta(1-42) aggregation (55.7%, at 5 microM) and acceptable neuroprotective activity. Extensive analysis of insvitro and insvivo assays indicates that new cyclopentaquinoline derivatives offer promise as candidates for new anti-AD drugs.
ESTHER : Czarnecka_2023_J.Enzyme.Inhib.Med.Chem_38_2158822
PubMedSearch : Czarnecka_2023_J.Enzyme.Inhib.Med.Chem_38_2158822
PubMedID: 36629422

Title : Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase - Jonczyk_2021_Biomolecules_11_
Author(s) : Jonczyk J , Kukulowicz J , Aatka K , Malawska B , Jung YS , Musilek K , Bajda M
Ref : Biomolecules , 11 : , 2021
Abstract : Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.
ESTHER : Jonczyk_2021_Biomolecules_11_
PubMedSearch : Jonczyk_2021_Biomolecules_11_
PubMedID: 33513955

Title : Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates - Lee_2021_J.Enzyme.Inhib.Med.Chem_36_437
Author(s) : Lee HM , Andrys R , Jonczyk J , Kim K , Vishakantegowda AG , Malinak D , Skarka A , Schmidt M , Vaskova M , Latka K , Bajda M , Jung YS , Malawska B , Musilek K
Ref : J Enzyme Inhib Med Chem , 36 :437 , 2021
Abstract : The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.
ESTHER : Lee_2021_J.Enzyme.Inhib.Med.Chem_36_437
PubMedSearch : Lee_2021_J.Enzyme.Inhib.Med.Chem_36_437
PubMedID: 33467931

Title : Discovery of multifunctional anti-Alzheimers agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and gamma-aminobutyric acid transporters - Pasieka_2021_Eur.J.Med.Chem_218_113397
Author(s) : Pasieka A , Panek D , Jonczyk J , Godyn J , Szalaj N , Latacz G , Tabor J , Mezeiova E , Chantegreil F , Dias J , Knez D , Lu J , Pi R , Korabecny J , Brazzolotto X , Gobec S , Hofner G , Wanner K , Wieckowska Q , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 218 :113397 , 2021
Abstract : Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: beta-secretase enzyme (BACE1) and amyloid beta (Abeta) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and gamma-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 microM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 microM; inhibition of Abeta aggregation = 57.9% at 10 microM; mGAT1 IC50 = 10.96 microM; and mGAT2 IC50 = 19.05 microM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 microM and IC50 = 2.95 microM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
ESTHER : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedSearch : Pasieka_2021_Eur.J.Med.Chem_218_113397
PubMedID: 33838585

Title : New Tetrahydroacridine Hybrids with Dichlorobenzoic Acid Moiety Demonstrating Multifunctional Potential for the Treatment of Alzheimer's Disease - Czarnecka_2020_Int.J.Mol.Sci_21_
Author(s) : Czarnecka K , Girek M , Wojtowicz P , Krecisz P , Skibinski R , Jonczyk J , Latka K , Bajda M , Walczak A , Galita G , Kabzinski J , Majsterek I , Szymczyk P , Szymanski P
Ref : Int J Mol Sci , 21 : , 2020
Abstract : A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, and evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, and 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition with IC50 values ranging from 24 to 607 nM. Among them, compound 3b was the most active (IC50 = 24 nM). Additionally, 3c (IC50 for EeAChE = 25 nM and IC50 for EqBuChE = 123 nM) displayed dual cholinesterase inhibitory activity and was the most active compound against acetylcholinesterase (AChE). Active compound 3c was also tested for the ability to inhibit Abeta aggregation. Theoretical physicochemical properties of the compounds were calculated using ACD Labs Percepta and Chemaxon. A Lineweaver-Burk plot and docking study showed that 3c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, 3c appears to possess neuroprotective activity and could be considered a free-radical scavenger. In addition, 3c did not cause DNA damage and was found to be less toxic than tacrine after oral administration; it also demonstrated little inhibitory activity towards hyaluronidase (HYAL), which may indicate that it possesses anti-inflammatory properties. The screening for new in vivo interactions between 3c and known receptors was realized by yeast three-hybrid technology (Y3H).
ESTHER : Czarnecka_2020_Int.J.Mol.Sci_21_
PubMedSearch : Czarnecka_2020_Int.J.Mol.Sci_21_
PubMedID: 32466601

Title : Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives-Anticancer and Cholinesterase-Inhibiting Activity - Jonczyk_2020_Molecules_25_
Author(s) : Jonczyk J , Godyn J , Stawarska E , Morak-Mlodawska B , Jelen M , Pluta K , Malawska B
Ref : Molecules , 25 : , 2020
Abstract : The inverse correlation observed between Alzheimer's disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 muM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 muM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 muM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.
ESTHER : Jonczyk_2020_Molecules_25_
PubMedSearch : Jonczyk_2020_Molecules_25_
PubMedID: 32503288

Title : Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer's disease - Szalaj_2020_J.Enzyme.Inhib.Med.Chem_35_1944
Author(s) : Szalaj N , Godyn J , Jonczyk J , Pasieka A , Panek D , Wichur T , Wieckowski K , Zareba P , Bajda M , Pislar A , Malawska B , Sabate R , Wieckowska A
Ref : J Enzyme Inhib Med Chem , 35 :1944 , 2020
Abstract : Effective therapy of Alzheimer's disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands - 5-HT(6) receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their beta-secretase, tau, and amyloid beta aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid beta aggregation in in cellulo assay of 59% and 56% at 10 microM, respectively, hBACE IC(50)=4 microM, h5TH6 K (i)=94 nM, hAChE IC(50)=26 nM, and eqBuChE IC(50)=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.
ESTHER : Szalaj_2020_J.Enzyme.Inhib.Med.Chem_35_1944
PubMedSearch : Szalaj_2020_J.Enzyme.Inhib.Med.Chem_35_1944
PubMedID: 33092411

Title : 1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer's disease - Wichur_2019_Eur.J.Med.Chem_187_111916
Author(s) : Wichur T , Wieckowska A , Wieckowski K , Godyn J , Jonczyk J , Valdivieso ADR , Panek D , Pasieka A , Sabate R , Knez D , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 187 :111916 , 2019
Abstract : Complex pathomechanism of Alzheimer's disease (AD) prompts researchers to develop multifunctional molecules in order to find effective therapy against AD. We designed and synthesized novel multifunctional ligands for which we assessed their activities towards butyrylcholinesterase, beta secretase, amyloid beta (Abeta) and tau protein aggregation as well as antioxidant and metal-chelating properties. All compounds showed dual anti-aggregating properties towards Abeta and tau protein in the in cellulo assay in Escherichia coli. Of particular interest are compounds 24b and 25b, which efficiently inhibit aggregation of Abeta and tau protein at 10 muM (24b: 45% for Abeta, 53% for tau; 25b: 49% for Abeta, 54% for tau). They display free radical scavenging capacity and antioxidant activity in ABTS and FRAP assays, respectively, and selectively chelate copper ions. Compounds 24b and 25b are also the most potent inhibitors of BuChE with IC50 of 2.39 muM and 1.94 muM, respectively. Promising in vitro activities of the presented multifunctional ligands as well as their original scaffold are a very interesting starting point for further research towards effective anti-AD treatment.
ESTHER : Wichur_2019_Eur.J.Med.Chem_187_111916
PubMedSearch : Wichur_2019_Eur.J.Med.Chem_187_111916
PubMedID: 31812794

Title : Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives - Jonczyk_2019_Bioorg.Chem_90_103084
Author(s) : Jonczyk J , Lodarski K , Staszewski M , Godyn J , Zareba P , Soukup O , Janockova J , Korabecny J , Salat K , Malikowska-Racia N , Hebda M , Szalaj N , Filipek B , Walczynski K , Malawska B , Bajda M
Ref : Bioorg Chem , 90 :103084 , 2019
Abstract : In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2=8.27), inhibitory activity against both AChE (IC50=13.96muM), and BuChE (IC50=14.62muM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
ESTHER : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedSearch : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedID: 31271942

Title : Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer's Disease - Czarnecka_2019_Int.J.Mol.Sci_20_
Author(s) : Czarnecka K , Girek M , Krecisz P , Skibinski R , Latka K , Jonczyk J , Bajda M , Kabzinski J , Majsterek I , Szymczyk P , Szymanski P
Ref : Int J Mol Sci , 20 : , 2019
Abstract : Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinami de hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky's rule of five.
ESTHER : Czarnecka_2019_Int.J.Mol.Sci_20_
PubMedSearch : Czarnecka_2019_Int.J.Mol.Sci_20_
PubMedID: 30678364

Title : Novel carbamate derivatives as selective butyrylcholinesterase inhibitors - Bajda_2018_Bioorg.Chem_78_29
Author(s) : Bajda M , Latka K , Hebda M , Jonczyk J , Malawska B
Ref : Bioorg Chem , 78 :29 , 2018
Abstract : Selective butyrylcholinesterase inhibitors could be the promising drug candidates, used in treatment of Alzheimer's disease. The study describes the synthesis and biological activity of novel carbamate derivatives with N-phenylpiperazine, N-benzylpiperazine and 4-benzylpiperidine moieties. Biological studies revealed that most of these compounds displayed significant activity against BuChE. Compound 16 (3-(4-phenyl-piperazin-1-ylmethyl)-phenyl phenylcarbamate) turned out to be the most active (IC50=2.00muM for BuChE). For all synthesized compounds lipophilicity and other physicochemical properties were calculated using computer programs. Relationship between these properties and activity was also checked. Binding mode with enzyme and the ensuing differences in activity were explained by the molecular modeling studies.
ESTHER : Bajda_2018_Bioorg.Chem_78_29
PubMedSearch : Bajda_2018_Bioorg.Chem_78_29
PubMedID: 29529519

Title : Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents - Panek_2018_Molecules_23_
Author(s) : Panek D , Wieckowska A , Pasieka A , Godyn J , Jonczyk J , Bajda M , Knez D , Gobec S , Malawska B
Ref : Molecules , 23 : , 2018
Abstract : The complex nature of Alzheimer's disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward beta-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human beta-secretase (hBACE-1), and beta-amyloid (Abeta-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 muM), hBACE-1 (43.7% at 50 muM), and Abeta-aggregation (24.9% at 10 muM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes-acetylcholinesterase and beta-secretase. IN CONCLUSION: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer's agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: beta-secretase and Abeta-aggregation.
ESTHER : Panek_2018_Molecules_23_
PubMedSearch : Panek_2018_Molecules_23_
PubMedID: 29414887

Title : Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment - Czarnecka_2018_Eur.J.Med.Chem_145_760
Author(s) : Czarnecka K , Chufarova N , Halczuk K , Maciejewska K , Girek M , Skibinski R , Jonczyk J , Bajda M , Kabzinski J , Majsterek I , Szymanski P
Ref : Eur Journal of Medicinal Chemistry , 145 :760 , 2018
Abstract : A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC50=1.02nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid beta (Abeta) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Abeta aggregation. Inhibition of Abeta aggregation was 46.63% and 19.41% at 50muM and 5muM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD.
ESTHER : Czarnecka_2018_Eur.J.Med.Chem_145_760
PubMedSearch : Czarnecka_2018_Eur.J.Med.Chem_145_760
PubMedID: 29353726

Title : Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents - Panek_2018_ACS.Chem.Neurosci_9_1074
Author(s) : Panek D , Wieckowska A , Jonczyk J , Godyn J , Bajda M , Wichur T , Pasieka A , Knez D , Pislar A , Korabecny J , Soukup O , Sepsova V , Sabate R , Kos J , Gobec S , Malawska B
Ref : ACS Chem Neurosci , 9 :1074 , 2018
Abstract : The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, beta-secretase, beta-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of beta-secretase (IC50 hBACE-1 = 41.60 muM), inhibition of amyloid beta aggregation (IC50 Abeta = 3.09 muM), inhibition of tau aggregation (55% at 10 muM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 muM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
ESTHER : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedSearch : Panek_2018_ACS.Chem.Neurosci_9_1074
PubMedID: 29345897

Title : New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer's disease - Czarnecka_2017_J.Enzyme.Inhib.Med.Chem_33_158
Author(s) : Czarnecka K , Girek M , Maciejewska K , Skibinski R , Jonczyk J , Bajda M , Kabzinski J , Solowiej P , Majsterek I , Szymanski P
Ref : J Enzyme Inhib Med Chem , 33 :158 , 2017
Abstract : Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of beta-amyloid (Abeta), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC50 value of 0.052 microM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC50 values from 0.071 to 0.797 microM. Compound 3b exhibited strong Abeta1-42 aggregation inhibitory effect with 25.7% at 5 microM to 92.8% at 100 microM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.
ESTHER : Czarnecka_2017_J.Enzyme.Inhib.Med.Chem_33_158
PubMedSearch : Czarnecka_2017_J.Enzyme.Inhib.Med.Chem_33_158
PubMedID: 29210299

Title : Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer's disease treatment - Czarnecka_2017_Bioorg.Chem_72_315
Author(s) : Czarnecka K , Szymanski P , Girek M , Mikiciuk-Olasik E , Skibinski R , Kabzinski J , Majsterek I , Malawska B , Jonczyk J , Bajda M
Ref : Bioorg Chem , 72 :315 , 2017
Abstract : A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 2-fluorobenzoic acid or 3-fluorobenzoic acid moiety were designed, synthesized and evaluated as inhibitors of cholinesterases and aggregation of beta-amyloid. In the study target compounds were very potent inhibitors of AChE and BChE. The most promising agents had higher inhibitory potency than the reference drugs which was tacrine. Ultimately, the kinetic assay shows the most active target compound 3c against AChE. Almost all of them were more potent against BChE than AChE. Compound 3c in various concentrations was tested by aggregation experiment. Inhibition of beta-amyloid aggregation was 77.32% and 80.43% at 50microM and 100microM, respectively. Therefore, compound 3c is a promising agent for the treatment of AD.
ESTHER : Czarnecka_2017_Bioorg.Chem_72_315
PubMedSearch : Czarnecka_2017_Bioorg.Chem_72_315
PubMedID: 28501648

Title : Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation - Panek_2016_Eur.J.Med.Chem_125_676
Author(s) : Panek D , Wieckowska A , Wichur T , Bajda M , Godyn J , Jonczyk J , Mika K , Janockova J , Soukup O , Knez D , Korabecny J , Gobec S , Malawska B
Ref : Eur Journal of Medicinal Chemistry , 125 :676 , 2016
Abstract : The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, beta-secretase and beta-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 muM to 19.18 muM. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 muM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 muM) and inhibitory activity against hBACE1 (33.61% at 50 muM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 muM) with BACE1 inhibitory activity (26.3% at 50 muM) and it displays the most significant Abeta anti-aggregating properties among all the obtained compounds (39% at 10 muM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
ESTHER : Panek_2016_Eur.J.Med.Chem_125_676
PubMedSearch : Panek_2016_Eur.J.Med.Chem_125_676
PubMedID: 27721153

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

Title : Therapeutic strategies for Alzheimer's disease in clinical trials - Godyn_2016_Pharmacol.Rep_68_127
Author(s) : Godyn J , Jonczyk J , Panek D , Malawska B
Ref : Pharmacol Rep , 68 :127 , 2016
Abstract : Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. Current treatment of the disease, essentially symptomatic, is based on three cholinesterase inhibitors and memantine, affecting the glutamatergic system. Since 2003, no new drugs have been approved for treatment of AD. This article presents current directions in the search for novel, potentially effective agents for the treatment of AD, as well as selected promising treatment strategies. These include agents acting upon the beta-amyloid, such as vaccines, antibodies and inhibitors or modulators of gamma- and beta-secretase; agents directed against the tau protein as well as compounds acting as antagonists of neurotransmitter systems (serotoninergic 5-HT6 and histaminergic H3). Ongoing clinical trials with Abeta antibodies (solanezumab, gantenerumab, crenezumab) seem to be promising, while vaccines against the tau protein (AADvac1 and ACI-35) are now in early-stage trials. Interesting results have also been achieved in trials involving small molecules such as inhibitors of beta-secretase (MK-8931, E2609), a combination of 5-HT6 antagonist (idalopirdine) with donepezil, inhibition of advanced glycation end product receptors by azeliragon or modulation of the acetylcholine response of alpha-7 nicotinic acetylcholine receptors by encenicline. Development of new effective drugs acting upon the central nervous system is usually a difficult and time-consuming process, and in the case of AD to-date clinical trials have had a very high failure rate. Most phase II clinical trials ending with a positive outcome do not succeed in phase III, often due to serious adverse effects or lack of therapeutic efficacy.
ESTHER : Godyn_2016_Pharmacol.Rep_68_127
PubMedSearch : Godyn_2016_Pharmacol.Rep_68_127
PubMedID: 26721364

Title : Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease - Bajda_2015_Bioorg.Med.Chem_23_5610
Author(s) : Bajda M , Jonczyk J , Malawska B , Czarnecka K , Girek M , Olszewska P , Sikora J , Mikiciuk-Olasik E , Skibinski R , Gumieniczek A , Szymanski P
Ref : Bioorganic & Medicinal Chemistry , 23 :5610 , 2015
Abstract : A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid beta aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50=19nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Abeta 1-42 aggregation (80.6% and 91.3% at 50muM and 100muM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD.
ESTHER : Bajda_2015_Bioorg.Med.Chem_23_5610
PubMedSearch : Bajda_2015_Bioorg.Med.Chem_23_5610
PubMedID: 26242241

Title : Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis, biological evaluation and molecular modeling studies - Mutahir_2015_Bioorg.Chem_64_13
Author(s) : Mutahir S , Jonczyk J , Bajda M , Khan IU , Khan MA , Ullah N , Ashraf M , Qurat Ul A , Riaz S , Hussain S , Yar M
Ref : Bioorg Chem , 64 :13 , 2015
Abstract : A series of new biphenyl bis-sulfonamide derivatives 2a-3p were synthesized in good to excellent yield (76-98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC50 0.04+/-0.0001muM for AChE) and (IC50 0.85+/-0.0001muM for BChE), the IC50 values of these compounds were ranged from 2.27+/-0.01 to 123.11+/-0.04muM for AChE and 7.74+/-0.07 to <400muM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC50 2.27+/-0.01muM), whereas 3g exhibited the highest inhibition for BChE (IC50 7.74+/-0.07muM). Structure-activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.
ESTHER : Mutahir_2015_Bioorg.Chem_64_13
PubMedSearch : Mutahir_2015_Bioorg.Chem_64_13
PubMedID: 26595185

Title : Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines - Lodarski_2015_J.Enzyme.Inhib.Med.Chem_30_98
Author(s) : Lodarski K , Jonczyk J , Guzior N , Bajda M , Gladysz J , Walczyk J , Jelen M , Morak-Mlodawska B , Pluta K , Malawska B
Ref : J Enzyme Inhib Med Chem , 30 :98 , 2015
Abstract : The study presents the discovery of novel butyrylcholinesterase (BCHE) inhibitors among derivatives of azaphenothiazines by application of in silico and in vitro screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand - AChE and ligand - BCHE). Five compounds displayed moderate AChE and good BCHE inhibitory activity at screening concentrations of 10 microM. The IC50 values for active BCHE inhibitors were in the 11.8-122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same N-methyl-2-piperidinethyl substituent.
ESTHER : Lodarski_2015_J.Enzyme.Inhib.Med.Chem_30_98
PubMedSearch : Lodarski_2015_J.Enzyme.Inhib.Med.Chem_30_98
PubMedID: 24666296

Title : New tacrine analogs as acetylcholinesterase inhibitors - theoretical study with chemometric analysis - Szymanski_2013_Molecules_18_2878
Author(s) : Szymanski P , Skibinski R , Inglot T , Bajda M , Jonczyk J , Malawska B , Mikiciuk-Olasik E
Ref : Molecules , 18 :2878 , 2013
Abstract : Computer simulations constitute the basis of the design and discovery of new drugs. This approach is not only significant with regards to finding new structures, but also for selecting the molecules with the highest probability of being useful in the diagnostic process and treatment of numerous diseases. In our work, we used computational software to analyze 32 new acetylcholinesterase (AChE) inhibitors and formulate ADMET predictions. To understand the influence of the structure of our derivatives on binding mode, we docked all structures to the active site of AChE and assigned some pharmacophoric features. Finally, we undertook a chemometric analysis of all the compounds on the basis of FT-IR, which gave us the possibility of performing a fast categorization of the analyzed compounds and design compounds with similar structures.
ESTHER : Szymanski_2013_Molecules_18_2878
PubMedSearch : Szymanski_2013_Molecules_18_2878
PubMedID: 23459299