Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
- MeSH
- antiflogistika chemie farmakokinetika farmakologie terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie MeSH
- cyklické nukleotidfosfodiesterasy, typ 7 antagonisté a inhibitory MeSH
- imidazoly chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesteras chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesterasy 4 chemie farmakokinetika farmakologie terapeutické užití MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- potkani Wistar MeSH
- pyridiny chemie farmakokinetika farmakologie terapeutické užití MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory aplikace a dávkování toxicita MeSH
- enzymatické testy MeSH
- hematoencefalická bariéra metabolismus MeSH
- hmotnostní spektrometrie MeSH
- hydrofobní a hydrofilní interakce MeSH
- imidazoly chemie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nosiče léků chemie MeSH
- otrava organofosfáty farmakoterapie MeSH
- oximy aplikace a dávkování farmakokinetika MeSH
- plocha pod křivkou MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny aplikace a dávkování farmakokinetika MeSH
- reaktivátory cholinesterasy aplikace a dávkování farmakokinetika MeSH
- sarin aplikace a dávkování toxicita MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We present the structural modification of a commercially available glass ionomer cement by inserting the imidazolium salt 1-n-hexadecyl-3-methylimidazolium chloride (C16MImCl), composing a new biomaterial with antifungal biofilm activity. Test specimens were prepared using a commercial glass ionomer cement to which 10 ppm of cetylpyridinium chloride (reference ionic antifungal agent) or C16MImCl were added. The feasibility and hypoallergenicity of the new biomaterial were assessed by microhardness plastic deformation and chorioallantoic membrane assays. Colony counting and scanning electron microscopy were used to evaluate the modified specimens' antibiofilm activity against three multidrug-resistant Candida species. The modified glass ionomer cement presented a strong antibiofilm activity against Candida spp., without losing its original micromechanical and hypoallergenic properties, rendering it a promising candidate for further application in dentistry.
Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.
- MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- imidazoly chemie metabolismus farmakologie MeSH
- inhibitory proteinkinas chemická syntéza metabolismus farmakologie MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza metabolismus farmakologie MeSH
- pyrimidiny chemie metabolismus farmakologie MeSH
- simulace molekulární dynamiky MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Ionic liquids are increasingly used for their superior properties. Four water-immiscible ionic liquids (butyltriethylammonium bis(trifluoromethylsulfonyl)imide, octyltriethylammonium bis(trifluoromethylsulfonyl)imide, dodecyltriethylammonium bis(trifluoromethylsulfonyl)imide, butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) and their water miscible precursors (bromides) were synthesized in a microwave reactor and by conventional heating. The best conditions for microwave-assisted synthesis concerning the yield and the purity of the product are proposed. The heating in the microwave reactor significantly shortened the reaction time. Biocide and ecotoxic effects of synthesized ionic liquids and their precursors were investigated. All tested compounds had at least a little effect on the growth or living of microorganisms (bacteria or mold). The precursor dodecyltriethylammonium bromide was found to be the strongest biocide, but posed a risk to the aquatic environment due to its relatively high EC50 value in the test with Vibrio fischeri. We assumed that apart from the alkyl chain length, the solubility in water, duration of action, or type of anion can influence the final biocide and ecotoxic effect.
- MeSH
- Aliivibrio fischeri účinky léků MeSH
- amoniové sloučeniny chemie MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- antifungální látky chemická syntéza chemie farmakologie MeSH
- ekotoxikologie metody MeSH
- imidazoly chemie MeSH
- iontové kapaliny chemická syntéza farmakologie MeSH
- kvartérní amoniové sloučeniny chemická syntéza farmakologie MeSH
- mikrovlny MeSH
- preklinické hodnocení léčiv metody MeSH
- Publikační typ
- časopisecké články MeSH
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
- MeSH
- atropin chemie MeSH
- hematoencefalická bariéra MeSH
- imidazoly chemie MeSH
- myši MeSH
- oximy chemie MeSH
- paraoxon chemie toxicita MeSH
- počítačová simulace MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny chemie MeSH
- reaktivátory cholinesterasy chemie toxicita MeSH
- simulace molekulového dockingu MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The present armamentarium of commercially available antidotes provides limited protection against the neurological effects of organophosphate exposure. Hence, there is an urgent need to design and develop molecules that can protect and reactivate inhibited-AChE in the central nervous system. Some natural compounds like glucose and certain amino acids (glutamate, the anion of glutamic acid) can easily cross the blood brain barrier although they are highly polar. Glucose is mainly transported by systems like glucose transporter protein type 1 (GLUT1). For this reason, a series of non-quaternary and quaternary glycosylated imidazolium oximes with different alkane linkers have been designed and synthesized. These compounds were evaluated for their in-vitro reactivation ability against pesticide (paraoxon-ethyl and paraoxon-methyl) inhibited-AChE and compared with standards antidote AChE reactivators pralidoxime and obidoxime. Several physicochemical properties including acid dissociation constant (pKa), logP, logD, HBD and HBA, have also been assessed for reported compounds. Out of the synthesized compounds, three have exhibited comparable potency with a standard antidote (pralidoxime).
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory toxicita MeSH
- Electrophorus metabolismus MeSH
- imidazoly chemická syntéza chemie farmakologie MeSH
- kinetika MeSH
- molekulární struktura MeSH
- oximy chemická syntéza chemie farmakologie MeSH
- pesticidy toxicita MeSH
- reaktivátory cholinesterasy chemická syntéza chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C1 to C18) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman's method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC50 values of 27.04-106.75 µM and 58.01-277.48 µM, respectively. Some compounds exhibited lower IC50 for AChE than the clinically used drug rivastigmine. N-Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C5 to C7 are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against Mycobacterium tuberculosis H37Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6).
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antiinfekční látky * chemická syntéza chemie farmakologie MeSH
- buňky Hep G2 MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory * chemická syntéza chemie farmakologie MeSH
- GPI-vázané proteiny metabolismus MeSH
- imidazoly * chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- Mycobacterium avium růst a vývoj MeSH
- Mycobacterium kansasii růst a vývoj MeSH
- Mycobacterium tuberculosis růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A novel magnetic-functionalized-multi-walled carbon nanotubes@chitosan N-heterocyclic carbene-palladium (M-f-MWCNTs@chitosan-NHC-Pd) nanocatalyst is developed in two steps. The first step entails the fabrication of a three-component cross-linking of chitosan utilizing the Debus-Radziszewski imidazole approach. The second step comprised the covalent grafting of prepared cross-linked chitosan to the outer walls of magnetically functionalized MWCNTs (M-f-MWCNTs) followed by introducing PdCl2 to generate the m-f-MWCNTs@cross-linked chitosan with a novel NHC ligand. The repeated units of the amino group in the chitosan polymer chain provide the synthesis of several imidazole units which also increase the number of Pd linkers thus leading to higher catalyst efficiency. The evaluation of catalytic activity was examined in the expeditious synthesis of biaryl compounds using the Suzuki cross-coupling reaction of various aryl halides and aryl boronic acids; ensuing results show the general applicability of nanocatalyst with superior conversion reaction yields, high turnover frequencies (TOFs) and turnover numbers (TON). Meanwhile, nanocatalyst showed admirable potential in reusability tests, being recycled for five runs without losing significant activities under optimum reaction conditions. The successfully synthesis of catalyst and its characterization was confirmed using the Fourier transform infrared spectrometer (FT-IR), spectrometer transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photo-electron spectroscopy (XPS) and thermogravimetric analysis (TGA).
- MeSH
- chitosan chemie MeSH
- imidazoly chemie farmakologie MeSH
- katalýza MeSH
- magnetické jevy * MeSH
- methan analogy a deriváty chemie MeSH
- nanotrubičky uhlíkové chemie MeSH
- palladium chemie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- termogravimetrie MeSH
- Publikační typ
- časopisecké články MeSH
This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H3, serotonin 5-HT3, 5-HT4, 5-HT6, dopamine D4, adenosine A2A, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.
- MeSH
- cílená molekulární terapie MeSH
- duševní poruchy farmakoterapie MeSH
- imidazoly chemie farmakologie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- ligandy MeSH
- neurodegenerativní nemoci farmakoterapie MeSH
- pyridiny chemie farmakologie terapeutické užití MeSH
- racionální návrh léčiv * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
