Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H37Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.03 μM), but also against M. kansasii (MIC ≥2 μM). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 μM. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better antimicrobial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.
- MeSH
- amidy chemie metabolismus farmakologie terapeutické užití MeSH
- aniliny chemie MeSH
- antituberkulotika chemická syntéza metabolismus farmakologie terapeutické užití MeSH
- bakteriální léková rezistence účinky léků MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- buňky Hep G2 MeSH
- kyselina pyrohroznová chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků metabolismus MeSH
- oxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- racionální návrh léčiv * MeSH
- tuberkulóza farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Roztroušená skleróza (RS) je chronické autoimunitní onemocnění centrálního nervového systému (CNS), které je charakterizované zánětlivým procesem, demyelinizací a neurodegenerativními změnami. V posledních letech došlo k výraznému rozšíření možností imunomodulační léčby RS. Původní skupina výhradně injekčních léků se rozrostla o léčiva infuzní a perorální. Postupné rozšíření léčebných možností dovoluje i větší zohlednění preferencí pacienta, přestože je volba konkrétního léku ovlivněna především aktivitou onemocnění, bezpečnostním profilem a přidruženými chorobami. V klinické praxi se u pacientů často setkáváme s preferencí perorálních léčiv. Prvním perorálním lékem schváleným pro léčbu relaps-remitentní RS byl fingolimod, který byl posléze doplněn dimethyl fumarátem a teriflunomidem. V současnosti je nejnověji k léčbě relaps- -remitentní RS schválen kladribin. Každý z léků má specifický mechanismus účinku, nežádoucí a vedlejší účinky. Také pozice ve stále složitějším algoritmu léčby RS je pro jednotlivé léky různá.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that is characterised by inflammatory process, demyelination, and neurodegenerative changes. Over the last years the options for immunomodulation therapy of MS have been greatly expanded. The original group of exclusively injection drugs has now additionally included infusion and oral drugs. Gradual expansion of treatment options allows also for increased consideration of patient preferences though the choice of a particular drug is mainly influenced by disease activity, its safety profile and accompanying diseases. It is quite common that patients in clinical practice prefer oral drugs. The first oral drug approved for therapy of relapsing- -remitting MS was fingolimod that has been later completed with dimethyl fumarate and teriflunomide. Currently the most recently approved drug for relapsing-remitting MS is cladribine. Each of the drugs has its specific mechanism of action, undesirable and side effects. Also their particular position in the ever more complex treatment algorithm of MS differs for individual drugs.
- MeSH
- dimethyl fumarát aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- fingolimod hydrochlorid aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- imunologické faktory aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- kladribin aplikace a dávkování farmakologie MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- oxidoreduktasy antagonisté a inhibitory MeSH
- receptory lysosfingolipidů antagonisté a inhibitory MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
Teriflunomid je v České republice registrován k léčbě roztroušené sklerózy (RS) ve stadiích klinicky izolovaného syndromu (CIS) a pro relabující-remitentní formu (RRRS). Teriflunomid má oproti stávajícím lékům nový mechanismus účinku. Inhibuje mitochondriální enzym dihydroorotát dehydrogenázu (DHODH) a tím blokuje syntézu pyrimidinu. Jeho účinnost byla prokázána v řadě klinických studií. Léčba tímto přípravkem je poměrně dobře snášena.
Teriflunomide is registered for treatment multiple sclerosis (MS) in Czech Republic in stages of clinically isolated syndrome (CIS) and relapsing-remitting MS (RR MS). Teriflunomide has a new mechanism of action. It inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and leads to blockade of the pyrimidine synthesis. The efficacy of teriflunomide has been shown in clinical trials. Teriflunomide is quite well tolerated.
- MeSH
- imunologické faktory * aplikace a dávkování ekonomika farmakokinetika škodlivé účinky MeSH
- klinické zkoušky jako téma MeSH
- lékové interakce MeSH
- lidé MeSH
- oxidoreduktasy antagonisté a inhibitory MeSH
- roztroušená skleróza * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/ 17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβ toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD's enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. Results and conclusions: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40μM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- benzothiazoly terapeutické užití MeSH
- guanidin terapeutické užití MeSH
- inhibitory enzymů chemická syntéza terapeutické užití MeSH
- lidé MeSH
- močovina terapeutické užití MeSH
- neuroprotektivní látky * chemická syntéza terapeutické užití MeSH
- oxidoreduktasy antagonisté a inhibitory škodlivé účinky MeSH
- příprava léků metody MeSH
- techniky in vitro metody MeSH
- thiomočovina terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinická studie MeSH
- práce podpořená grantem MeSH
KEY MESSAGE: Two new TDZ derivatives (HETDZ and 3FMTDZ) are very potent inhibitors of CKX and are promising candidates for in vivo studies. Cytokinin hormones regulate a wide range of essential processes in plants. Thidiazuron (N-phenyl-N'-1,2,3-thiadiazol-5-yl urea, TDZ), formerly registered as a cotton defoliant, is a well known inhibitor of cytokinin oxidase/dehydrogenase (CKX), an enzyme catalyzing the degradation of cytokinins. TDZ thus increases the lifetime of cytokinins and their effects in plants. We used in silico modeling to design, synthesize and characterize twenty new TDZ derivatives with improved inhibitory properties. Two compounds, namely 1-[1,2,3]thiadiazol-5-yl-3-(3-trifluoromethoxy-phenyl)urea (3FMTDZ) and 1-[2-(2-hydroxyethyl)phenyl]-3-(1,2,3-thiadiazol-5-yl)urea (HETDZ), displayed up to 15-fold lower IC 50 values compared with TDZ for AtCKX2 from Arabidopsis thaliana and ZmCKX1 and ZmCKX4a from Zea mays. Binding modes of 3FMTDZ and HETDZ were analyzed by X-ray crystallography. Crystal structure complexes, solved at 2.0 Å resolution, revealed that HETDZ and 3FMTDZ bound differently in the active site of ZmCKX4a: the thiadiazolyl ring of 3FMTDZ was positioned over the isoalloxazine ring of FAD, whereas that of HETDZ had the opposite orientation, pointing toward the entrance of the active site. The compounds were further tested for cytokinin activity in several cytokinin bioassays. We suggest that the combination of simple synthesis, lowered cytokinin activity, and enhanced inhibitory effects on CKX isoforms, makes 3FMTDZ and HETDZ suitable candidates for in vivo studies.
The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects.
- MeSH
- anthrachinony farmakologie MeSH
- antibiotika antitumorózní farmakologie MeSH
- chemorezistence účinky léků MeSH
- daunomycin farmakologie MeSH
- emodin farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- oxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- simulace molekulového dockingu MeSH
- synergismus léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chronic exposure to trichothecenes is known to disturb insulin-like growth factor 1 and signaling of insulin and leptin hormones and causes considerable growth retardation in animals. However, limited information was available on mechanisms underlying trichothecene-induced growth retardation. In this study, we employed an integrated transcriptomics, proteomics, and RNA interference (RNAi) approach to study the molecular mechanisms underlying trichothecene cytotoxicity in rat pituitary adenoma GH3 cells. Our results showed that trichothecenes suppressed the synthesis of growth hormone 1 (Gh1) and inhibited the eukaryotic transcription and translation initiation by suppressing aminoacyl-tRNA synthetases transcription, inducing eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) and reducing eukaryotic translation initiation factor 5 a. The sulfhydryl oxidases , protein disulfide isomerase,and heat shock protein 90 (were greatly reduced, which resulted in adverse regulation of protein processing and folding. Differential genes and proteins associated with a decline in energy metabolism and cell cycle arrest were also found in our study. However, use of RNAi to interfere with hemopoietic cell kinase (Hck) and EIF2AK2 transcriptions or use of chemical inhibitors of MAPK, p38, Ras, and JNK partially reversed the reduction of Gh1 levels induced by trichothecenes. It indicated that the activation of MAPKs, Hck, and EIF2AK2 were important for trichothecene-induced growth hormone suppression. Considering the potential hazards of exposure to trichothecenes, our findings could help to improve our understanding regarding human and animal health implications.
- MeSH
- aminoacyl-tRNA-synthetasy antagonisté a inhibitory MeSH
- apoptóza účinky léků MeSH
- buněčné linie MeSH
- genetická transkripce účinky léků MeSH
- iniciační faktory antagonisté a inhibitory MeSH
- kinasa eIF-2 antagonisté a inhibitory MeSH
- krysa rodu rattus MeSH
- oxidoreduktasy antagonisté a inhibitory MeSH
- proteindisulfidisomerasy antagonisté a inhibitory MeSH
- proteiny tepelného šoku HSP90 antagonisté a inhibitory MeSH
- proteiny vázající RNA antagonisté a inhibitory MeSH
- proteomika * MeSH
- proteosyntéza účinky léků MeSH
- RNA interference účinky léků MeSH
- růstový hormon antagonisté a inhibitory MeSH
- stanovení celkové genové exprese * MeSH
- T-2 toxin analogy a deriváty farmakologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.
- MeSH
- aminy chemie MeSH
- aniliny chemie MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- atypické mykobakteriální infekce mikrobiologie MeSH
- azoly chemie MeSH
- bakteriální léková rezistence MeSH
- bakteriální proteiny antagonisté a inhibitory chemie MeSH
- cyklizace MeSH
- isoniazid analogy a deriváty chemická syntéza farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium avium účinky léků enzymologie růst a vývoj MeSH
- Mycobacterium kansasii účinky léků enzymologie růst a vývoj izolace a purifikace MeSH
- Mycobacterium tuberculosis účinky léků enzymologie růst a vývoj MeSH
- oxidoreduktasy antagonisté a inhibitory chemie MeSH
- pyridiny chemie MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mikroorganizmy sú známe svojou schopnosťou produkovať bioaktívne sekundárne metabolity, ktoré sa často využívajú v klinickej praxi nielen ako antibiotiká. Tieto zlúčeniny sa vyznačujú mnohými biologickými aktivitami, dôležitými v terapii nádorových chorôb, zápalových ochorení, autoimunitných a metabolických porúch. Veda a medicínske výskumy priniesli veľa nových a užitočných poznatkov z oblasti terapie závažných chorôb spôsobených patofyziologickou aktivitou niektorých enzýmov, čo sa ako súčasná problematika neustále študuje mnohými výskumnými vedeckými odborníkmi. Veľa látok bolo objavených ešte v minulom storočí, avšak ich potenciál a rôzne modifikácie zlepšujúce ich perspektívu na terapeutické využitie neustále pokračuje. Nové poznatky v oblasti enzymológie o enzýmových inhibítoroch a mechanizmoch účinkov dávajú priestor na objavy nových farmakoterapeutík, ktoré budú účinnejšie a menej toxické.
Microorganisms are known for their production of an enormous variety of biologically active secondary metabolites including antibiotics, immunosuppressants and anticancer agents. These compounds have many important biological activities used in the clinical practice in drug treatment of cancer, inflammatory, autoimmune diseases and metabolic disorders. The science and medicine research have been yielded hundreds items of useful knowledge in the therapy of many serious human diseases caused by pathophysiological mechanisms of enzymes. Many substances were discovered already in the last century, but the research of their potential and various modifications improving their prospects of therapeutic use still continues. The new knowledge about mechanisms of the action and enzyme inhibitors in the field of enzymology gives space in drug discovery and development of safer and more effective pharmacotherapy.
- MeSH
- enzymy MeSH
- farmakologie klinická MeSH
- lidé MeSH
- oxidoreduktasy antagonisté a inhibitory MeSH
- transferasy antagonisté a inhibitory MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Anthracycline cardiotoxicity represents the most unfavorable side effect of these highly efficient anticancer drugs. Several biotransformation enzymes have been described to contribute to their cardiotoxicity. Besides the activities of CYP450 isoforms which lead to the generation of reactive oxygen species (ROS), the cytosolic reductases have attracted attention nowadays. The reductases known to metabolize anthracyclines to C13-hydroxyanthracyclines are carbonyl reductase (CR, 1.1.1.184) and the aldo-keto reductases (AKR1C2, 1.3.1.20; AKR1A1, 1.1.1.2). Their participation in the formation of the toxic C13-hydroxymetabolite has been investigated in rabbit using diagnostic inhibitors of CR and AKR1C2. The kinetics and the type of reductase inhibition exerted by the two inhibitors have been described and it was found that CR was the main daunorubicin reductase at both optimal and physiological pH with the kinetic parameters for daunorubicin reduction of Km = 17.01 +/- 1.98 microM and V(max) = 139.60 +/- 5.64 pcat/mg. The IC50 values for quercitrin and flufenamic acid were 5.45 +/- 1.37 microM and 3.68 +/- 1.58 microM, respectively. The inhibition was uncompetitive for both inhibitors and irreversible in the case of flufenamic acid.
- MeSH
- cytosol enzymologie MeSH
- daunomycin chemie toxicita MeSH
- financování organizované MeSH
- inhibiční koncentrace 50 MeSH
- játra cytologie enzymologie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- králíci MeSH
- molekulární struktura MeSH
- oxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
