Barbara Malawska

Barbara Malawska
Jagiellonian University | UJ · Faculty of Pharmacy (Medical College)

About

182
Publications
27,959
Reads
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3,780
Citations
Additional affiliations
October 1973 - April 2021
Jagiellonian University
Position
  • Professor
Description
  • 2020 - currently professor at the Department of Physicochemical Drug Analysis Faculty of Pharmacy Jagiellonian University in Kraków 2005 - 2020 Head of Department of Physicochemical Drug Analysis Chair of Pharmaceutical Chemistry Faculty of Pharmacy Jagiellonian University in Kraków 2003-2008 Vice-Dean of the Faculty of Pharmacy Jagiellonian University 1998 - Habilitation, Jagiellonian University 1983 - Ph. D., Pharmacy, Medical Academy, Kraków
Education
October 1968 - July 1973
Jagiellonian University
Field of study
  • chemistry
October 1968 - June 1973
Jagiellonian University
Field of study
  • chemistry

Publications

Publications (182)
Article
Full-text available
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)...
Article
Full-text available
Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this contex...
Article
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 de...
Article
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 β-amyloid aggregation. Structure-activi...
Article
Full-text available
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....
Article
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 gaine...
Article
Full-text available
In Alzheimer's disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-b...
Article
γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Followin...
Article
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 prev...
Article
Full-text available
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 o...
Article
Full-text available
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-HT6 receptor antagonists and cholinesterase inhibitors – with disease-modifying properties. We have p...
Article
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 H3 receptor (H3R) antagonists/inverse agonists, and virtual docking w...
Article
Full-text available
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 tetr...
Article
Full-text available
Profiling blood-brain barrier permeability of bioactive molecule is an important issue in early drug development, being a part of the optimization process of a compound's physicochemical properties, and hence pharmacokinetic profile. The study aimed to develop and optimize a new in vitro method for assessment of the compound's brain penetration. Th...
Article
γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that...
Article
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate, but selective hBu...
Article
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 (Aβ) and tau protein aggregation as we...
Article
Full-text available
Neurotransmitter γ-aminobutyric acid (GABA) plays a principal role in the regulation of mammalian central nervous system functions. GABA evoked neurotransmission is terminated by a rapid uptake via dependent plasma membrane GABA transporters (GATs) located in the cell membrane. Potent inhibitors of these GATs are of fundamental importance for eluci...
Article
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...
Article
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-pro...
Article
Full-text available
Background Bis-pyridinium aldoximes are reactivators of the paraoxon-inhibited butyrylcholinesterase enzyme. Paraoxon is the active product of parathion, a widely used insecticide. Objective The objective of this study is to examine the dose-dependent distribution of K117, a bis-pyridinium aldoxime in rat tissues. Materials and Methods White male...
Article
Full-text available
Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer’s disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attr...
Article
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 di...
Article
Full-text available
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...
Article
Alzheimer’s disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. Complexity of AD pathomechanism requires complex treatment e.g. multifunctional ligands targeting both causes and symptoms of the disease. Here, we present new multi-target-directed ligands combining pha...
Article
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, β-secretase, β-amyloid and t...
Article
Full-text available
The crucial role of G-protein coupled receptors and the significant achievements associated with a better understanding of the spatial structure of known receptors in this family encouraged us to undertake a study on the histamine H3 receptor, whose crystal structure is still unresolved. The latest literature data and availability of different soft...
Data
ChemPLP score for the best pose of each ligand after docking with GOLD. Colors represent the individual ligands: A331440—purple, A349821—orange, ABT 239—gray, Ciproxifan—yellow, Clobenpropit—red, JNJ520785—green, Thioperamide—blue. (TIF)
Data
Average RMSD value between all poses of each ligand in each docking. Colors represent the individual ligands: A331440—purple, A349821—orange, ABT 239—gray, Ciproxifan—yellow, Clobenpropit—red, JNJ520785—green, Thioperamide—blue. (TIF)
Data
Alignment of H3 receptor sequence from UniProt (UniProt Entry: Q9Y5N1) with rM3R template sequence (PDB: 4U15) used to prepare of the best model. (TIF)
Data
BCL::Score and QMEAN score values for 21 models chosen for docking with GOLD. BCL::Score values are represented by green bars, QMEAN score are represented by red lozenge. (TIF)
Data
Number of “successfully” docked ligand pose after docking with GOLD. Ligands placed within the orthosteric and/or allosteric site are called “successfully” docked. Colors represent the individual ligands: A331440—purple, A349821—orange, ABT 239—gray, Ciproxifan—yellow, Clobenpropit—red, JNJ520785—green, Thioperamide—blue. (TIF)
Data
Detailed parameters of homology modeling process with the programs Modeller, Jackal and the web-services I-Tasser, Swis-Model. # Template and modeling parameters used for the best model. * H—UniProt sequences of human histamine receptors H1-H4, M—UniProt sequences of human muscarinic receptors M1-M5, H3 –UniProt sequence of hH3R, 3RZE—sequence of h...
Data
Detailed list of ligands from GLL and GDD datasets with activity tags. (DOCX)
Data
Absolute values of GlideScore for each docking. Colors represent the individual ligands: A331440—purple, A349821—orange, ABT 239—gray, Ciproxifan—yellow, Clobenpropit—red, JNJ520785—green, Thioperamide—blue. (TIF)
Article
The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review de...
Article
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 β-amyloid. In the study target compounds were very potent inhibitors of AChE and BChE. The most promising agents had higher inhibitory...
Article
Lipophilicity as one of the most important physicochemical properties of the biologically active compounds is closely related to their pharmacokinetic parameters and therefore, it is taken into account at the design stage of new drugs. Among the novel, fast and reliable methods for determination of the lipophilicity of compounds micellar electrokin...
Article
Full-text available
Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the di...
Article
Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amin...
Article
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 desi...
Article
Background: The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. Methods: The target compounds 8-12 were prepared in one step from the 4-substi...
Article
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 done...
Article
Full-text available
We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity,...
Article
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 hista...
Article
Full-text available
Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention...
Article
Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed lib...
Article
Given the complex nature of Alzheimer's disease (AD), compounds that are able to simultaneously address two or more AD-associated targets show greater promise for development into drugs for AD therapy. Herein we report an efficient two-step synthesis and biological evaluation of new racemic benzochromene derivatives as antioxidants, inhibitors of c...
Article
In an effort to develop α-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The α1 - and α2 -adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward α1...
Article
Full-text available
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 treatmen...
Article
A virtual screening of the ZINC database was applied for the identification of novel cholinesterase inhibitors. The first step allowed to select compounds with favorable physicochemical properties. Then, the compounds were screened with the pharmacophore models built using crystal structures of donepezil, tacrine, decamethonium and bis-7-tacrine wi...
Article
There is a strong medical demand to search for novel, more efficacious and safer than available, analgesics for the treatment of neuropathic pain. This study investigated antinociceptive activity of intraperitoneally administered 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) and pregabalin in the chronic constriction inj...
Article
Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitor...
Article
Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and β-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticho...
Article
Alzheimer's disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer's disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and β-amylo...
Article
Full-text available
Selective drugs directed at a single biological target often prove ineffective in the treatment of diseases with a complex pathomechanism, e.g. Alzheimer's disease (AD). This situation prompts researchers to design multi-target-directed ligands (MTDLs), capable of interacting with a number of selected biological targets. The paper outlines the conc...
Article
Full-text available
Neuropathic pain is a drug resistant type of chronic pain and there is a strong medical demand to search for novel analgesically active compounds for its alleviation. In the present paper we investigated antihyperalge-sic properties of 3-[4-(3-trifl uoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one (LPP1) in a mouse model of toxic polyneuropath...
Article
Full-text available
Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactori...