Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).
- MeSH
- antituberkulotika chemie MeSH
- COVID-19 * MeSH
- dánio pruhované MeSH
- kyselina aminosalicylová * farmakologie MeSH
- laktony MeSH
- lidé MeSH
- Mycobacterium tuberculosis * MeSH
- myši MeSH
- pyrazinamid farmakologie MeSH
- SARS-CoV-2 MeSH
- tuberkulóza * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).
- MeSH
- antituberkulotika chemie MeSH
- isoniazid farmakologie MeSH
- kyselina aminosalicylová * farmakologie MeSH
- lidé MeSH
- methionin MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- myši MeSH
- tuberkulóza * farmakoterapie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dospělí MeSH
- komorbidita MeSH
- lidé MeSH
- nádory prsu komplikace MeSH
- orbitocelulitida * diagnóza etiologie klasifikace mikrobiologie MeSH
- prokain penicilin G aplikace a dávkování terapeutické užití MeSH
- Staphylococcus aureus patogenita MeSH
- Streptococcus pyogenes patogenita MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Syphilis je systémová infekce s mnohočetnými projevy, které mohou napodobovat široké spektrum kožních i jiných nemocí. Důležitá je včasná diagnostika i vhodně zvolená antibiotická léčba.
Syphilis is a systemic infection with multiple manifestations that can mimic a wide range of skin and other diseases. Early diagnosis and appropriate antibiotic treatment are important.
- MeSH
- benzathin-penicilin G aplikace a dávkování terapeutické užití MeSH
- doxycyklin aplikace a dávkování terapeutické užití MeSH
- homosexualita mužská MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymerázová řetězová reakce MeSH
- prokain penicilin G aplikace a dávkování terapeutické užití MeSH
- rizikový sex MeSH
- sérologická diagnostika syfilis MeSH
- sexuálně přenosné nemoci diagnóza farmakoterapie MeSH
- syfilis * diagnóza farmakoterapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Mycobacterium tuberculosis is an intracellular pathogen and the uptake of the antimycobacterial compounds by host cells is limited. Novel antimycobacterials effective against intracellular bacteria are needed. New N-substituted derivatives of 4-aminosalicylic acid have been designed and evaluated. To achieve intracellular efficacy and selectivity, these compounds were conjugated to tuftsin peptides via oxime or amide bonds. These delivery peptides can target tuftsin- and neuropilin receptor-bearing cells, such as macrophages and various other cells of lung origin. We have demonstrated that the in vitro antimycobacterial activity of the 4-aminosalicylic derivatives against M. tuberculosis H37Rv was preserved in the peptide conjugates. The free drugs were ineffective on infected cells, but the conjugates were active against the intracellular bacteria and have the selectivity on various types of host cells. The intracellular distribution of the carrier peptides was assessed, and the peptides internalize and display mainly in the cytosol in a concentration-dependent manner. The penetration ability of the most promising carrier peptide OT5 was evaluated using Transwell-inserts and spheroids. The pentapeptide exhibited time- and concentration-dependent penetration across the non-contact monolayers. Also, the pentapeptide has a fair penetration rate towards the center of spheroids formed of EBC-1 cells.
- MeSH
- antibakteriální látky farmakologie MeSH
- antituberkulotika chemie farmakologie MeSH
- kyselina aminosalicylová * farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- peptidy chemie MeSH
- pomocné látky farmakologie MeSH
- tuftsin * chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antibakteriální látky aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- lidé MeSH
- polymerázová řetězová reakce MeSH
- prokain penicilin G aplikace a dávkování terapeutické užití MeSH
- sérologická diagnostika syfilis metody MeSH
- sexuálně přenosné nemoci diagnóza farmakoterapie MeSH
- syfilis kožní diagnóza farmakoterapie MeSH
- syfilis * diagnóza farmakoterapie MeSH
- Treponema pallidum MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Prokinetika patří v gastroenterologii k poměrně bohatě využívaným léčivým přípravkům. Terapeuticky se uplatňují u řady patologických stavů, mezi nimiž dominuje funkční dyspepsie. V této indikaci nalézá své uplatnění itoprid. Následující text stručně pojednává o jeho současném postavení v paletě prokinetik vycházejícím z jeho obecně známých farmakologických vlastností.
Prokinetics are one of the relatively widely used medicinal products in gastroenterology. They are used therapeutically in a number of pathological conditions, among which functional dyspepsia predominates. Itopride was approved in this indication. Hence, the following text briefly discusses its current position in a variety of prokinetics based on its well-known pharmacological properties.
- Klíčová slova
- itoprid,
- MeSH
- antagonisté dopaminu D2 terapeutické užití MeSH
- benzamidy * farmakokinetika farmakologie terapeutické užití MeSH
- cholinesterasové inhibitory terapeutické užití MeSH
- domperidon terapeutické užití MeSH
- dyspepsie * farmakoterapie MeSH
- gastroezofageální reflux farmakoterapie MeSH
- gastrointestinální motilita účinky léků MeSH
- metoklopramid terapeutické užití MeSH
A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 μM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 μM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- analýza hlavních komponent MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie MeSH
- inhibiční koncentrace 50 MeSH
- karbamáty farmakologie MeSH
- kyselina aminosalicylová chemie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- racionální návrh léčiv MeSH
- rozpouštědla MeSH
- shluková analýza MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu * MeSH
- THP-1 buňky MeSH
- viabilita buněk MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Tento přehledový článek má za cíl informovat o relativně nové zajímavé alternativě lokální anestezie v zubním lékařství. Jedná se o metodu názální aplikace spreje, který obsahuje lokální anestetikum tetrakain v kombinaci s vasokonstriktorem oxymetazolinem. Stručně jsou zde popsány obě účinné látky a zejména hlavní výhody a nevýhody této nové aplikační formy s důrazem na její praktické využití.
The aim of this review is to inform about a relatively new interesting alternative of local anesthesia in dentistry. This method is based on nasal application of spray containing local anesthetic tetracain combined with vasoconstrictor oxymetazolin. This review briefly describes both active ingredients and especially mentions major advantages and disadvantages of this new applicaion form accenting its practical use.
