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 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 β-secretase (IC50  hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50  hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein účinky léků   metabolismus   MeSH
• butyrylcholinesterasa farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• proteiny tau účinky léků   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulového dockingu metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, 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.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• objevování léků * MeSH
• proteiny přenášející GABA přes plazmatickou membránu metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• multifunkční psychotika,
• MeSH
• antidepresiva * farmakologie   terapeutické užití   MeSH
• antipsychotika * farmakologie   terapeutické užití   MeSH
• duševní poruchy farmakoterapie   MeSH
• lidé MeSH
• receptory serotoninové účinky léků   MeSH
• selektivní inhibitory zpětného vychytávání serotoninu farmakologie   terapeutické užití   MeSH
• trazodon farmakokinetika   farmakologie   terapeutické užití   MeSH
• vztah mezi dávkou a účinkem léčiva * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

The aim of this study was to investigate the restorative connections of composite materials after fracture, under controlled conditions of treating the materials with novel, spherosilicate-based (SS) primers bearing both methacryl (MA) and trimethoxysilyl (TMOS) groups. The chemistry of methacrylate group insertion and reactive groups hydrolysis has been studied with the aid of 1H NMR (Nuclear Magnetic Resonance) spectroscopy. The light-cured resin composites were repaired by activating the connection site with the obtained primers and, for comparison, a silane (methacryloxypropyltrimethoxysilane, MATMOS) as a conventional coupling agent bearing the same reactive groups. The resistance of such a joint was tested in a three-point bending test after 24 h and 28 days period of sample conditioning. The effect of bond application was also studied, showing that spherosilicate-based primers may be used more effectively than MATMOS for two-step (primer-composite) restorative process, while for silane, the three-step process with bond application is crucial for satisfactory joint quality. The joint failure mode was determined by microscopic analysis and it was found that SS-4MA-4TMOS and SS-2MA-6TMOS application resulted in mostly composite, and not joint, failure. After 28 days of conditioning, the flexural strength of the joint repaired with SS-4MA-4TMOS was at 94% of the neat, solid material under the same procedure. However, the strength of the neat composite was observed to decline during the conditioning process by ~30%. The joint behavior was explained on the basis of the gradual hydrolysis effect (the greatest decrease being observed for silane).

• Publikační typ
• časopisecké články MeSH

Combining different antimicrobial agents has emerged as a promising strategy to enhance efficacy and address resistance evolution. In this study, we investigated the synergistic antimicrobial effect of a cationic biobased polymer and the antimicrobial peptide (AMP) temporin L, with the goal of developing multifunctional electrospun fibers for potential biomedical applications, particularly in wound dressing. A clickable polymer with pendent alkyne groups was synthesized by using a biobased itaconic acid building block. Subsequently, the polymer was functionalized through click chemistry with thiazolium groups derived from vitamin B1 (PTTIQ), as well as a combination of thiazolium and AMP temporin L, resulting in a conjugate polymer-peptide (PTTIQ-AMP). The individual and combined effects of the cationic PTTIQ, Temporin L, and PTTIQ-AMP were evaluated against Gram-positive and Gram-negative bacteria as well as Candida species. The results demonstrated that most combinations exhibited an indifferent effect, whereas the covalently conjugated PTTIQ-AMP displayed an antagonistic effect, potentially attributed to the aggregation process. Both antimicrobial compounds, PTTIQ and temporin L, were incorporated into poly(lactic acid) electrospun fibers using the supercritical solvent impregnation method. This approach yielded fibers with improved antibacterial performance, as a result of the potent activity exerted by the AMP and the nonleaching nature of the cationic polymer, thereby enhancing long-term effectiveness.

• MeSH
• alkyny MeSH
• antibakteriální látky * farmakologie   MeSH
• gramnegativní bakterie * MeSH
• grampozitivní bakterie MeSH
• kationty MeSH
• polymery farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• buněčné linie MeSH
• butyrylcholinesterasa metabolismus   MeSH
• chinoliny chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• Cricetulus MeSH
• lidé MeSH
• molekulární struktura MeSH
• takrin chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

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 = 13.96 μM), and BuChE (IC50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.

• MeSH
• acetylcholinesterasa chemie   MeSH
• adjuvancia anestetická toxicita   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amnézie chemicky indukované   farmakoterapie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• ligandy MeSH
• modely nemocí na zvířatech * MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši MeSH
• piperaziny chemie   MeSH
• receptory histaminu H3 chemie   metabolismus   MeSH
• skopolamin toxicita   MeSH
• techniky in vitro MeSH
• výpočetní biologie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH

Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• buňky Hep G2 MeSH
• HeLa buňky MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mnohočetný myelom farmakoterapie   enzymologie   MeSH
• proliferace buněk účinky léků   fyziologie   MeSH
• vyvíjení léků metody   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Infectious diseases caused by new or unknown bacteria and viruses, such as anthrax, cholera, tuberculosis and even COVID-19, are a major threat to humanity. Thus, the development of new synthetic compounds with efficient antimicrobial activity is a necessity. Herein, rationally designed novel multifunctional cationic alternating copolymers were directly synthesized through a step-growth polymerization reaction using a bivalent electrophilic cross-linker containing disulfide bonds and a diamine heterocyclic ring. To optimize the activity of these alternating copolymers, several different diamines and cross-linkers were explored to find the highest antibacterial effects. The synthesized nanopolymers not only displayed good to excellent antibacterial activity as judged by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli, but also reduced the number of biofilm cells even at low concentrations, without killing mammalian cells. Furthermore, in vivo experiments using infected burn wounds in mice demonstrated good antibacterial activity and stimulated wound healing, without causing systemic inflammation. These findings suggest that the multifunctional cationic nanopolymers have potential as a novel antibacterial agent for eradication of multidrug resistant bacterial infections.

• MeSH
• aminy chemie   MeSH
• antibakteriální látky farmakologie   MeSH
• antiflogistika nesteroidní farmakologie   MeSH
• Bacteria účinky léků   MeSH
• bakteriální infekce farmakoterapie   etiologie   MeSH
• biofilmy účinky léků   MeSH
• COVID-19 MeSH
• HEK293 buňky účinky léků   MeSH
• hojení ran účinky léků   MeSH
• kationty farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mnohočetná bakteriální léková rezistence účinky léků   MeSH
• myši MeSH
• polymery chemie   farmakologie   MeSH
• popálení komplikace   MeSH
• reagencia zkříženě vázaná MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotoxicity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhibited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced conversion of tilimycin to tilivalline, and activation of PXR. IMPORTANCE The human gut harbors a complex community of microbes, including several species and strains that could be commensals or pathogens depending on context. The specific environmental conditions under which a resident microbe changes its relationship with a host and adopts pathogenic behaviors, in many cases, remain poorly understood. Here, we describe a novel communication network involving the regulation of K. grimontii and K. oxytoca enterotoxicity. Bacterial indole was identified as a central modulator of these colitogenic microbes by suppressing bacterial toxin (tilimycin) synthesis and converting tilimycin to tilivalline while simultaneously activating a host receptor, PXR, as a means of mitigating tissue cytotoxicity. On the other hand, fermentable carbohydrates were found to inhibit indole biosynthesis and enhance toxin production. This integrated network involving microbial, host, and metabolic factors provides a contextual framework to better understand K. oxytoca complex pathogenicity.

• MeSH
• cytotoxiny metabolismus   MeSH
• enterotoxiny metabolismus   MeSH
• indoly metabolismus   MeSH
• infekce bakteriemi rodu Klebsiella * mikrobiologie   MeSH
• Klebsiella oxytoca genetika   metabolismus   MeSH
• lidé MeSH
• novorozenec MeSH
• pseudomembranózní enterokolitida * mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH