The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• fenoly chemická syntéza   chemie   farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• salicylanilidy chemická syntéza   chemie   farmakologie   MeSH
• tuberkulóza farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The COVID-19 pandemic caused by SARS-CoV-2 virus has created a global damage and has exposed the vulnerable side of scientific research towards novel diseases. The intensity of the pandemic is huge, with mortality rates of more than 6 million people worldwide in a span of 2 years. Considering the gravity of the situation, scientists all across the world are continuously attempting to create successful therapeutic solutions to combat the virus. Various vaccination strategies are being devised to ensure effective immunization against SARS-CoV-2 infection. SARS-CoV-2 spreads very rapidly, and the infection rate is remarkably high than other respiratory tract viruses. The viral entry and recognition of the host cell is facilitated by S protein of the virus. N protein along with NSP3 is majorly responsible for viral genome assembly and NSP12 performs polymerase activity for RNA synthesis. In this study, we have designed a multi-epitope, chimeric vaccine considering the two structural (S and N protein) and two non-structural proteins (NSP3 and NSP12) of SARS-CoV-2 virus. The aim is to induce immune response by generating antibodies against these proteins to target the viral entry and viral replication in the host cell. In this study, computational tools were used, and the reliability of the vaccine was verified using molecular docking, molecular dynamics simulation and immune simulation studies in silico. These studies demonstrate that the vaccine designed shows steady interaction with Toll like receptors with good stability and will be effective in inducing a strong and specific immune response in the body.Communicated by Ramaswamy H. Sarma.

• MeSH
• COVID-19 * prevence a kontrola   MeSH
• epitopy B-lymfocytární MeSH
• lidé MeSH
• pandemie prevence a kontrola   MeSH
• reprodukovatelnost výsledků MeSH
• SARS-CoV-2 metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vakcíny proti COVID-19 MeSH
• virové vakcíny * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) has a complex pathophysiology that includes aggregation of pathological proteins, impaired neurotransmission, increased oxidative stress, or microglia-mediated neuroinflammation. Therapeutics targeting only one of these AD-related subpathologies have not yet been successful in the search for a disease-modifying treatment. Therefore, multi-target drugs (MTDs) aiming simultaneously at several subpathologies are expected to be a better approach. However, the concept of MTD is inherently connected with several limitations, which are often ignored during MTD design and development. Here, we provide an overview of the MTD approach and discuss its potential pitfalls in the context of AD treatment. We also put forward ideas to be used in the rational design of MTDs to obtain drugs that are effective against AD.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• léčivé přípravky * MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• nervový přenos MeSH
• oxidační stres MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• antioxidancia chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• donepezil chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• hematoencefalická bariéra diagnostické zobrazování   metabolismus   MeSH
• indany chemie   MeSH
• lidé MeSH
• ligandy * MeSH
• nádorové buněčné linie MeSH
• neuroprotektivní látky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• oxidační stres účinky léků   MeSH
• proteinové agregáty účinky léků   MeSH
• racionální návrh léčiv MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The factors and mechanisms involved in vacuolar transport in plants, and in particular those directing vesicles to their target endomembrane compartment, remain largely unknown. To identify components of the vacuolar trafficking machinery, we searched for Arabidopsis modified transport to the vacuole (mtv) mutants that abnormally secrete the synthetic vacuolar cargo VAC2. We report here on the identification of 17 mtv mutations, corresponding to mutant alleles of MTV2/VSR4, MTV3/PTEN2A MTV7/EREL1, MTV8/ARFC1, MTV9/PUF2, MTV10/VPS3, MTV11/VPS15, MTV12/GRV2, MTV14/GFS10, MTV15/BET11, MTV16/VPS51, MTV17/VPS54, and MTV18/VSR1 Eight of the MTV proteins localize at the interface between the trans-Golgi network (TGN) and the multivesicular bodies (MVBs), supporting that the trafficking step between these compartments is essential for segregating vacuolar proteins from those destined for secretion. Importantly, the GARP tethering complex subunits MTV16/VPS51 and MTV17/VPS54 were found at endoplasmic reticulum (ER)- and microtubule-associated compartments (EMACs). Moreover, MTV16/VPS51 interacts with the motor domain of kinesins, suggesting that, in addition to tethering vesicles, the GARP complex may regulate the motors that transport them. Our findings unveil a previously uncharacterized compartment of the plant vacuolar trafficking pathway and support a role for microtubules and kinesins in GARP-dependent transport of soluble vacuolar cargo in plants.

• MeSH
• alely MeSH
• Arabidopsis genetika   metabolismus   MeSH
• cytoplazmatické vezikuly genetika   metabolismus   MeSH
• endoplazmatické retikulum genetika   metabolismus   MeSH
• Golgiho aparát genetika   metabolismus   MeSH
• kineziny genetika   metabolismus   MeSH
• mikrotubuly genetika   metabolismus   MeSH
• multivezikulární tělíska genetika   metabolismus   MeSH
• mutace MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• transport proteinů genetika   MeSH
• vakuoly genetika   metabolismus   MeSH
• vezikulární transportní proteiny genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• Cricetulus MeSH
• HEK293 buňky MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• kapilární permeabilita MeSH
• kyselina glutamová metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• memantin chemická syntéza   farmakologie   MeSH
• neuroprotektivní látky chemická syntéza   farmakologie   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• techniky tkáňových kultur MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• dexamethason farmakokinetika   MeSH
• endoplazmatické retikulum genetika   patologie   účinky léků   MeSH
• glukokortikoidy farmakokinetika   genetika   klasifikace   MeSH
• lidé MeSH
• nefrotický syndrom etiologie   genetika   metabolismus   MeSH
• transport proteinů fyziologie   genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

• MeSH
• dexamethason farmakokinetika   MeSH
• endoplazmatické retikulum genetika   patologie   účinky léků   MeSH
• glukokortikoidy farmakokinetika   genetika   klasifikace   MeSH
• lidé MeSH
• nefrotický syndrom etiologie   genetika   metabolismus   MeSH
• transport proteinů fyziologie   genetika   imunologie   MeSH
• tunikamycin farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.

• MeSH
• acetylcholin nedostatek   MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• buněčné linie MeSH
• buňky PC12 MeSH
• cholinesterasové inhibitory chemie   MeSH
• inhibitory cyklooxygenasy 2 chemie   MeSH
• inhibitory lipoxygenas chemie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• neurony účinky léků   enzymologie   patologie   MeSH
• racionální návrh léčiv MeSH
• semikarbazidy chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• triazoly chemie   farmakologie   MeSH
• zánět farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• Anacardium chemie   metabolismus   MeSH
• buněčné linie MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• katalytická doména MeSH
• lidé MeSH
• ligandy * MeSH
• lipopolysacharidy farmakologie   MeSH
• mikroglie cytologie   účinky léků   metabolismus   MeSH
• neuroprotektivní látky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• ořechy chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• rostlinné extrakty chemie   MeSH
• simulace molekulární dynamiky MeSH
• takrin chemie   metabolismus   MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH