Damijan Knez
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View article: Expanding the reactive chemistry toolbox – warhead screening for covalent butyrylcholinesterase inhibitors
Expanding the reactive chemistry toolbox – warhead screening for covalent butyrylcholinesterase inhibitors Open
Many covalent inhibitors of butyryl- and acetylcholinesterase, typically featuring electrophilic carbamoyl, phosphonyl, and sulfonyl groups, were reported in the literature. In this study, we screened these and several other electrophilic …
View article: Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor
Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and α7 nicotinic receptor Open
Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple…
View article: N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer’s disease
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer’s disease Open
As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promisin…
View article: Transforming ureas into carbamates: From allosteric p38α MAPK ligands to dual BChE/p38α MAPK inhibitors
Transforming ureas into carbamates: From allosteric p38α MAPK ligands to dual BChE/p38α MAPK inhibitors Open
Given the limited benefits of anticholinergic drugs and the repeated clinical failures of anti-amyloid therapies, the therapeutic focus in Alzheimer's disease (AD) is gradually shifting toward addressing both disease symptoms and its major…
View article: Tunable nucleofugality in carbamoyl-bearing covalent cholinesterase inhibitors
Tunable nucleofugality in carbamoyl-bearing covalent cholinesterase inhibitors Open
A handful of carbamate warheads is utilised in chemical biology to target serine hydrolases. The following case study on cholinesterases is the first comprehensive structure- reactivity exploration of the carbamoyl warhead, rather than one…
View article: Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors
Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors Open
The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers a…
View article: N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors
N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors Open
Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors a…
View article: Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease
Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease Open
Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inh…
View article: Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer’s disease
Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer’s disease Open
View article: Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer’s Disease
Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer’s Disease Open
Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound 2, a racemic, nanomolar BChE inhibitor…
View article: Biochemical characteristics of the 6-nitro regioisomer of nitroxoline and its 1,2,3,4-tetrahydroquinoline analogues
Biochemical characteristics of the 6-nitro regioisomer of nitroxoline and its 1,2,3,4-tetrahydroquinoline analogues Open
A significant amount of data about the different pharmacological activities of the established antimicrobial compound nitroxoline (8-hydroxy-5-nitroquinoline) is available in the scientific literature. On the other hand, its regioisomer 8-…
View article: α-Heteroarylthiomethyl ketones: Small molecule inhibitors of 3CL<sup>pro</sup>
α-Heteroarylthiomethyl ketones: Small molecule inhibitors of 3CL<sup>pro</sup> Open
The main protease 3CL pro of the SARS-CoV-2 virus is a well--established therapeutic target for the treatment of COVID-19. In this study, we screened an in-house compound library and identified a series of α-heteroarylthiomethyl ketones as…
View article: Facile Synthesis of Carbamoyl Fluorides <i>via</i> <i>N</i>-Carbamoylimidazole Activation
Facile Synthesis of Carbamoyl Fluorides <i>via</i> <i>N</i>-Carbamoylimidazole Activation Open
The untapped potential of carbamoyl fluorides for various chemico/biological applications is hampered by the scarcity of straightforward and benign methods for their synthesis. In this report, we disclose a novel mild three-step procedure …
View article: Access to amidines <i>via</i> C(sp<sup>2</sup>)–N coupling of trifluoroborate-iminiums with <i>N</i>-fluorobenzenesulfonimide
Access to amidines <i>via</i> C(sp<sup>2</sup>)–N coupling of trifluoroborate-iminiums with <i>N</i>-fluorobenzenesulfonimide Open
Primary trifluoroborate-iminiums are transformed into N -sulfonyl amidines in an azide- and transition-metal-free C(sp 2 )–N bond-forming reaction under mild conditions. The mechanism was elucidated via NMR, mass spectrometry and DFT calcu…
View article: Azide- and Transition-Metal-Free Access to Sulfonyl Amidines via C(sp2)-N Coupling of Trifluoroborate-Iminiums with N-Fluorobenzenesulfonimide
Azide- and Transition-Metal-Free Access to Sulfonyl Amidines via C(sp2)-N Coupling of Trifluoroborate-Iminiums with N-Fluorobenzenesulfonimide Open
Amidines are an important class of organic compounds with widespread application as superbases, nucleophilic cata-lysts, and building blocks of heterocyclic compounds in organic synthesis. Moreover, they represent an important struc-tural …
View article: Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease
Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease Open
The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We pro…
View article: Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson’s disease
Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson’s disease Open
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of monoamine oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxi…
View article: Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with <i>In Vitro</i> and <i>In Vivo</i> Activity in Neurodegenerative Diseases
Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with <i>In Vitro</i> and <i>In Vivo</i> Activity in Neurodegenerative Diseases Open
Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of…
View article: Synthesis and biochemical evaluation of new 3-amido-4-substituted monocyclic ß-lactams as inhibitors of penicillin-binding protein(s)
Synthesis and biochemical evaluation of new 3-amido-4-substituted monocyclic ß-lactams as inhibitors of penicillin-binding protein(s) Open
In the final phases of bacterial cell wall synthesis, penicillin-binding proteins (PBPs) catalyze the cross-linking of peptidoglycan. For many decades, effective and non-toxic β-lactam antibiotics have been successfully used as mimetics of…
View article: Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid β detection
Probing Alzheimer's pathology: Exploring the next generation of FDDNP analogues for amyloid β detection Open
Fluorescent probes are a powerful tool for imaging amyloid β (Aβ) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties …
View article: Analiza in nadzor zdravil: Učno gradivo za vaje
Analiza in nadzor zdravil: Učno gradivo za vaje Open
Pri vajah iz Analize in nadzora zdravil se ne ukvarjamo le z enačbami in laboratorijskimi napravami; gre tudi za razvoj zavesti o natančnosti, odgovornosti in etičnem ravnanju. Gre za ključ k razumevanju farmacevtske analize zdravil, kjer …
View article: Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds
Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds Open
Synthesis and anticholinesterase activity of 18 previously unpublished indole- and tryptophan-derived compounds are disclosed. These compounds containing an indole structural unit exhibit selective submicromolar inhibition of human butyryl…
View article: Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones
Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones Open
Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cy…
View article: SMALL FLUORESCENT MOLECULAR PROBES FOR DETECTION OF CONFORMATIONAL PATHOLOGY
SMALL FLUORESCENT MOLECULAR PROBES FOR DETECTION OF CONFORMATIONAL PATHOLOGY Open
View article: Tunable Heteroaromatic Nitriles for Selective Bioorthogonal Click Reaction with Cysteine
Tunable Heteroaromatic Nitriles for Selective Bioorthogonal Click Reaction with Cysteine Open
The binucleophilic properties of 1,2-aminothiol and its rare occurrence in nature make it a useful reporter for tracking molecules in living systems. The 1,2-aminothiol moiety is present in cysteine, which is a substrate for a biocompatibl…
View article: 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases
8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases Open
View article: Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities—The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice
Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities—The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice Open
Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we pr…
View article: Pseudo-irreversible butyrylcholinesterase inhibitors: Structure–activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead
Pseudo-irreversible butyrylcholinesterase inhibitors: Structure–activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead Open
View article: Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors
Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors Open
Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocy…
View article: Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?
Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe? Open
Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused libr…