Bondzic AM

References (6)

Title : Targeting Alzheimer's Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates - Jovanovic_2024_Int.J.Mol.Sci_25_
Author(s) : Jovanovic D , Filipovic A , Janjic G , Lazarevic-Pasti T , Dzambaski Z , Bondzic BP , Bondzic AM
Ref : Int J Mol Sci , 25 : , 2024
Abstract : We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes' inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB.
ESTHER : Jovanovic_2024_Int.J.Mol.Sci_25_
PubMedSearch : Jovanovic_2024_Int.J.Mol.Sci_25_
PubMedID: 38256107

Title : Cytotoxic activity and influence on acetylcholinesterase of series dinuclear platinum(II) complexes with aromatic nitrogen-containing heterocyclic bridging ligands: Insights in the mechanisms of action - Bondzic_2021_Chem.Biol.Interact__109708
Author(s) : Bondzic AM , akula JJ , Koricanac LB , Keta OD , Janjic GV , Dorevic IS , Rajkovic SU
Ref : Chemico-Biological Interactions , :109708 , 2021
Abstract : Herein, the stability, lipophilicity, in vitro cytotoxicity, and influence on acetylcholinesterase of five dinuclear platinum(II) complexes with the general formula [{Pt(en)Cl}(2)(micro-L)](2+) (L is a different aromatic nitrogen-containing heterocyclic bridging ligands pyrazine (pz, Pt1), pyridazine (pydz, Pt2), quinoxaline (qx, Pt3), phthalazine (phtz, Pt4) and quinazoline (qz, Pt5), while en is bidentate coordinated ethylenediamine) were evaluated. The most active analyzed platinum complexes induced time-dependent growth inhibition of A375, HeLa, PANC-1, and MRC-5 cells. The best efficiency was achieved on HeLa and PANC-1 cells for Pt1, Pt2, and Pt3 at the highest concentration, while Pt1 was significantly more potent than cisplatin at a lower concentration. Additionally, a lower effect on normal cells was observed compared to cisplatin, which may indicate potentially fewer side effects of these complexes. Selected complexes induce reactive oxygen species and apoptosis on tumor cell lines. The most potent reversible acetylcholinesterase (AChE) inhibitors were Pt2, Pt4, and Pt5. Pt1 showed similar inhibitory effects toward AChE as cisplatin, but a different type of inhibition, which could contribute to lower neurotoxicity. Docking studies revealed that Pt2 and Pt4 were bound to the active gorge above the catalytic triad. In contrast, the other complexes were bound to the edge of the active gorge without impeding the approach to the catalytic triad. According to this, Pt1 represents a promising compound with potent anticancer properties, high selectivity, and low neurotoxicity.
ESTHER : Bondzic_2021_Chem.Biol.Interact__109708
PubMedSearch : Bondzic_2021_Chem.Biol.Interact__109708
PubMedID: 34666020

Title : A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules - the role in the mechanism of AChE inhibition - Bondzic_2020_Eur.J.Pharm.Sci_151_105376
Author(s) : Bondzic AM , Lazarevic-Pasti TD , Leskovac AR , Petrovic SZ , Colovic MB , Parac-Vogt TN , Janjic GV
Ref : Eur J Pharm Sci , 151 :105376 , 2020
Abstract : Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors, 12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate (POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism and tryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significant changes in the secondary structure of the enzyme. The molecular docking approach has revealed a new allosteric binding site, termed beta-allosteric site (beta-AS), which is considered responsible for the inhibition of AChE by POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is considered responsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selected POMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. It was shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, which indicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable of binding to an allosteric site that so far has not been considered responsible for enzyme inhibition could be fundamental for the development of new drug design strategies and the discovery of more efficient AChE modulators.
ESTHER : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedSearch : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedID: 32492460

Title : Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action - Bondzic_2020_J.Inorg.Biochem_205_110990
Author(s) : Bondzic AM , Sencanski MV , Vujacic Nikezic AV , Kirillova MV , Andre V , Kirillov AM , Bondzic BP
Ref : J Inorg Biochem , 205 :110990 , 2020
Abstract : Three coordination compounds featuring different types of tetracopper(II) cores, namely [O subsetCu4{N(CH2CH2O)3}4(BOH)4][BF4]2 (1), [Cu4(mu4-H2edte)(mu5-H2edte)(sal)2]n.7nH2O, (H4edte=N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine, H2sal=salicylic acid) (2), and [{Cu4(mu3-Hbes)4(mu-hba)}K(H2O)3]n, H3bes=N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (3), were assayed for their potency to inhibit the acetyl (AChE) and butyrylcholinesterase (BuChE) enzymes aiming to test these compounds as potential dual inhibitors in the treatment of Alzheimer's disease. All the investigated compounds showed a strong inhibitory potency toward both enzymes with IC50 values in micromolar range of concentration; compound 1 displayed the most potent inhibitory behaviour toward both enzymes. The mechanism of the AChE and BuChE inhibition was examined by enzyme kinetic measurements. The obtained kinetic parameters, Vmax and Km indicated an uncompetitive type of inhibition of both enzymes by compound 1. For the other two compounds a non-competitive inhibition mode was observed. To get further insight into the mechanism of action and to elucidate binding modes in details we examined the interactions of 1-3 with acetylcholinesterase, using molecular docking approach. Grid based docking studies indicated that these compounds can bind to peripheral anionic site (PAS) of the AChE with Ki values in micromolar range. Moreover, blind docking revealed the capability of investigated compounds to bind to new allosteric site (i.e. binding site II) distinct from PAS. Showing that these Cu-based compounds can act as new allosteric inhibitors of AChE and identifying novel allosteric binding site on AChE represents a significant contribution toward the design of novel and more effective inhibitors of AChE.
ESTHER : Bondzic_2020_J.Inorg.Biochem_205_110990
PubMedSearch : Bondzic_2020_J.Inorg.Biochem_205_110990
PubMedID: 32035286

Title : Acetylcholinesterase inhibitors: pharmacology and toxicology - Colovic_2013_Curr.Neuropharmacol_11_315
Author(s) : Colovic MB , Krstic DZ , Lazarevic-Pasti TD , Bondzic AM , Vasic VM
Ref : Curr Neuropharmacol , 11 :315 , 2013
Abstract : Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.
ESTHER : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedSearch : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedID: 24179466

Title : Indirect electrochemical oxidation of organophosphorous pesticides for efficient detection via acetylcholinesterase test - Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236
Author(s) : Lazarevic-Pasti TD , Bondzic AM , Pasti IA , Vasic VM
Ref : Pesticide Biochemistry and Physiology , 104 :236 , 2012
Abstract : Organothiophosphorous pesticides diazinon, malathion, chlorpyrifos, azinphos-methyl and phorate, have been indirectly electrochemically oxidized in aqueous media using anodically evolved Cl2, Br2 or I2 as a pre-step for their detection via acetylcholinesterase-based test. The presence of single oxidation product, corresponding oxo-form, was confirmed by UPLC analysis, as well as its stability with respect to hydrolysis. Comparing different halogens, the best results were obtained using Br2 as the oxidant due to high reactivity of HOBr, which is formed upon chemical reaction of anodically formed Br2 with water. Limits of detection of five analyzed pesticides were lowered upon indirect electrochemical oxidation with Br2 for two orders of magnitude or more, comparing to unoxidized parental thio-forms. In fact, the lowest possible detection limits for all five pesticides using proposed analytical procedure were achieved, as being determined by detection limits of corresponding oxo forms. Comparison of here proposed electrochemical oxidation pre-step with earlier reported ones is provided and discussed.
ESTHER : Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236
PubMedSearch : Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236
PubMedID: