Urease inhibitors
Dotaz
Zobrazit nápovědu
Vnásledujícím souhrnu je uveden přehled dostupné literatury na aktuální téma týkající se enzymu ureasy. Ureasa je enzym katalyzující hydrolýzu močoviny. Vpřehledu je diskutován výskyt ureasy, její funkce avýznam arovněž role ureasy aureolytických bakterií vpatogenezi různých onemocnění. Jsou prezentovány známé anorganické ipřírodní inhibitory ureasy. Práce se zabývá důležitostí hledání nových inhibitorů ureasy apotenciálem přírodních látek vtéto oblasti.
In this review, an overview of the available literature on urease is presented. Urease is an enzyme which catalyzes the hydrolysis of urea. The occurrence of ureases and their functions are discussed thoroughly. The relationship of urease to ureolytic bacteria is examined, and the currently available urease inhibitors, both inorganic and natural, are presented. Finally, the importance of urease and current and future applications of new inhibitors and explored.
- MeSH
- Helicobacter pylori imunologie patogenita MeSH
- inhibitory enzymů klasifikace MeSH
- Klebsiella imunologie patogenita MeSH
- lidé MeSH
- moč * mikrobiologie MeSH
- močové ústrojí * mikrobiologie MeSH
- močovina * MeSH
- nádory farmakoterapie MeSH
- Proteus imunologie patogenita MeSH
- rostlinné extrakty MeSH
- ureasa * antagonisté a inhibitory fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Inhibition of the metalloenzyme urease has important pharmacologic applications in the field of antiulcer and antigastric cancer agents. Urease is involved in many serious infections caused by Helicobacter pylori in the gastric tract as well as by Proteus and related species in the urinary tract. Although numerous studies have described several novel urease inhibitors (UIs) used for the treatment of gastric and urinary infections, all these compounds have exhibited severe side effects, toxicity, and instability. Therefore, to overcome such problems, it is necessary to search for new sources of UIs, such as natural products, that provide reduced side effects, low toxicity, greater stability, and bioavailability. As limited studies have been conducted on plant-derived UIs, this paper aims to highlight and summarize the most promising compounds isolated and identified from plants, such as terpenoids, phenolic compounds, alkaloids, and other substances with inhibitory activities against plant and bacterial ureases; these are in vitro and in vivo studies with an emphasis on structure-activity relationship studies and types of inhibition that show high and promising levels of anti-urease activity. This will aid medicinal chemists in the design and synthesis of novel and pharmacologically potent UIs useful for the development of antiulcer drugs.
The increasing resistance of pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications, has stimulated the development of novel classes of molecules that target urease as an enzyme. In this context, the newly developed compounds on the basis of 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity to validate their role as potent inhibitors of this enzyme. 1-Heptanoyl-3-arylthioureas were obtained in excellent yield and characterized through spectral and elemental analysis. All the compounds displayed remarkable potency against urease inhibition as compared to thiourea standard. It was found that novel compounds fulfill the criteria of drug-likeness by obeying Lipinski's rule of five. Particularly compound 4a and 4c can serve as lead molecules in 4D (drug designing discovery and development). Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity of the molecules.
- MeSH
- Canavalia enzymologie MeSH
- inhibitory enzymů chemie farmakologie MeSH
- kinetika MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu * MeSH
- thiomočovina chemie farmakologie MeSH
- ureasa antagonisté a inhibitory metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
AIMS: The aim of the present research was to synthesize glycoluril derivative 2,4-Bis(4- cyanobenzyl)glycoluril through a convergent scheme. BACKGROUND: For this purpose, Sandmeyer reaction procedure was employed for the synthesis of said compound. The structure of the pure compound was confirmed by using different spectroscopic techniques, such as 1HNMR, 13C-NMR and (HR-MS) Mass spectrometry. OBJECTIVE: Convergent synthesis of 2,4-BIS (4-CYANOBENZYL)GLYCOLURIL USING SANDMEYER REACTION and urease inhibition study. METHODS: The structure of the pure compound was confirmed by using different spectroscopic techniques such as 1H-NMR, 13C-NMR and (HR-MS) Mass spectrometry. The electronic properties of the newly synthesized compound and thiourea were determined by using density functional theory. RESULTS: Furthermore, the compound was evaluated against urease enzyme and was found to be potent inhibitors with an IC50 value of 11.5 ± 1.50 μM when compared with standard inhibitor thiourea (IC50 = 21.0 ± 1.90 μM). The compound may serve as a lead compound to synthesize new cyano-based bambusuril in the future with enhanced biological properties. CONCLUSION: We have synthesized a new glycoluril derivative 2,4-Bis(4-cyanobenzyl)glycoluril by the sandmeyer reaction. It has been obtained in the form of light yellowish powder in good yield (96%). Glycoluril based macrocycles have been used in various fields; starting from the 2,4-Bis(4-nitrobenzyl)glycoluril (already reported compound), which has undergone reduction (CH3OH,Pt/C) , diazotization (NaNO2/HCl), cyanation (CuCl/KCN), respectively in order to synthesize the desired new glycoluril derivative. The obtained product will be used as a building block for the synthesis of the cyano based bambusuril marcocycle in the future. The yield of the obtained product has been monitored by using different amounts of cyanating reagent, but the best results are shown by the use of 4 mmol of CuCl/KCN. KCN with CuCl assisted the conversion of diazo group into the cyano group with enhanced yield when used in excess amount. It acts as a catalyst. The solubility characteristic of 2,4-Bis(4-cyanobenzyl)glycoluril has also been determined in different organic solvents. 1H NMR technique proved to be very helpful for the structure determination of our desired product. Benzylic protons give signals at 7.5 ppm and 7.8 ppm, respectively. The downfield peaks confirm the presence of CN group near the benzylic protons. Methine protons show a signal at 5.2 ppm, which ensures the basic skeleton of glycoluril. Ureidyl protons also confirm the synthesis of the heterocyclic 2,4-Bis(4-cyanobenzyl)glycoluril compound. The negative and positive electrostatic potential sites, molecular descriptors, and charge density distribution of frontier molecular orbitals are revealing that 4a with promising sites for electrophilic and nucleophilic attacks would result to enhance the urease inhibition, which is in good agreement with the experimental data.
Furan chalcone scaffolds belong to the most privileged and promising oxygen-containing heterocyclic class of compounds, which have a wide spectrum of therapeutic applications in the field of pharmaceutics, pharmacology, and medicinal chemistry. This research described the synthesis of a series of twelve novel and seven reported furan chalcone (conventional synthetic approach) analogues 4a-s through the application of microwave-assisted synthetic methodology and evaluated for therapeutic inhibition potential against bacterial urease enzyme. In the first step, a series of nineteen substituted 5-aryl-2-furan-2-carbaldehyde derivatives 3a-s were achieved in moderate to good yields (40-70%). These substituted 5-aryl-2-furan-2-carbaldehyde derivatives 3a-s were condensed with acetophenone via Claisen-Schmidt condensation to furnish 19 substituted furan chalcone scaffolds 4a-s in excellent yields (85-92%) in microwave-assisted synthetic approach, while in conventional methodology, these furan chalcone 4a-s were furnished in good yield (65-90%). Furan chalcone structural motifs 4a-s were characterized through elemental analysis and spectroscopic techniques. These nineteen (19)-afforded furan chalcones 4a-s were screened for urease inhibitory chemotherapeutic efficacy and most of the furan chalcones displayed promising urease inhibition activity. The most active urease inhibitors were 1-phenyl-3-[5-(2',5'-dichlorophenyl)-2-furyl]-2-propen-1-one 4h with an IC50 value of 16.13 ± 2.45 μM, and 1-phenyl- 3-[5-(2'-chlorophenyl)-2-furyl] -2-propen-1-one 4s with an IC50 value of 18.75 ± 0.85 μM in comparison with reference drug thiourea (IC50 = 21.25 ± 0.15 μM). These furan chalcone derivatives 4h and 4s are more efficient urease inhibitors than reference drug thiourea. Structure-activity relationship (SAR) revealed that the 2,5-dichloro 4h and 2-chloro 4s moiety containing furan chalcone derivatives may be considered as potential lead reagents for urease inhibition. The in silico molecular docking study results are in agreement with the experimental biological findings. The results of this study may be helpful in the future drug discovery and designing of novel efficient urease inhibitory agents from this biologically active class of furan chalcones.
- Publikační typ
- časopisecké články MeSH
Studies on enzyme inhibition remain a crucial area in drug discovery since these studies have led to the discoveries of new lead compounds useful in the treatment of several diseases. In this study, protocatechuic acid (PCA), an active compound from Hibiscus sabdariffa L. has been evaluated for its inhibitory properties against jack bean urease (JBU) as well as its possible toxic effect on human gastric epithelial cells (GES-1). Anti-urease activity was evaluated by an Electrospray Ionization-Mass Spectrometry (ESI-MS) based method, while cytotoxicity was assayed by the MTT method. PCA exerted notable anti-JBU activity compared with that of acetohydroxamic acid (AHA), with IC50 values of 1.7 and 3.2 µM, respectively. PCA did not show any significant cytotoxic effect on (GES-1) cells at concentrations ranging from 1.12 to 3.12 µM. Molecular docking study revealed high spontaneous binding ability of PCA to the active site of urease. Additionally, the anti-urease activity was found to be related to the presence of hydroxyl moieties of PCA. This study presents PCA as a natural urease inhibitor, which could be used safely in the treatment of diseases caused by urease-producing bacteria.
- MeSH
- buněčné linie MeSH
- Hibiscus chemie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- hydroxybenzoáty chemie MeSH
- kyseliny hydroxamové chemie MeSH
- lidé MeSH
- simulace molekulového dockingu metody MeSH
- ureasa antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
For decades, Hibiscus sabdariffa L. and its phytochemicals have been shown to possess a wide range of pharmacologic properties. In this study, aqueous extract of Hibiscus sabdariffa (AEHS) and its bioactive constituent protocatechuic acid (PCA), have been evaluated in vitro for their antiviral activity against HSV-2 clinical isolates and anti-enzymatic activity against urease. Antiherpetic activity was evaluated by the titer reduction assay in infected Vero cells, and cytotoxicity was evaluated by the neutral red dye-uptake method. Anti-urease activity was determined by a developed Electrospray Ionization-Mass Spectrometry (ESI-MS)-based assay. PCA showed potent anti-HSV-2 activity compared with that of acyclovir, with EC50 values of 0.92 and 1.43 µg∙mL(-1), respectively, and selectivity indices > 217 and > 140, respectively. For the first time, AEHS was shown to exert anti-urease inhibition activity, with an IC50 value of 82.4 µg∙mL(-1). This, combined with its safety, could facilitate its use in practical applications as a natural urease inhibitor. Our results present Hibiscus sabdariffa L. and its bioactive compound PCA as potential therapeutic agents in the treatment of HSV-2 infection and the treatment of diseases caused by urease-producing bacteria.
- MeSH
- acyklovir farmakologie MeSH
- antivirové látky chemie izolace a purifikace farmakologie MeSH
- Cercopithecus aethiops MeSH
- Hibiscus chemie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů chemie izolace a purifikace farmakologie MeSH
- kinetika MeSH
- lidský herpesvirus 2 účinky léků MeSH
- polyfenoly chemie izolace a purifikace farmakologie MeSH
- preklinické hodnocení léčiv MeSH
- rostlinné extrakty chemie izolace a purifikace farmakologie MeSH
- ureasa antagonisté a inhibitory chemie MeSH
- Vero buňky MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans-N,N'-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC50 28.7 μM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC50 336.8 μM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC50 values in the lower micromolar region.
- MeSH
- buňky Hep G2 MeSH
- DNA metabolismus chemie MeSH
- fluor chemie MeSH
- komplexní sloučeniny * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- ligandy MeSH
- měď * chemie MeSH
- protinádorové látky * farmakologie chemie MeSH
- Schiffovy báze * chemie farmakologie MeSH
- sérový albumin hovězí chemie MeSH
- ureasa antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Garlic is a well-known example of natural self-defence system consisting of an inactive substrate (alliin) and enzyme (alliinase) which, when combined, produce highly antimicrobial allicin. Increase of alliinase stability and its activity are of paramount importance in various applications relying on its use for in-situ synthesis of allicin or its analogues, e.g., pulmonary drug delivery, treatment of superficial injuries, or urease inhibitors in fertilizers. Here, we discuss the effect of temperature, pH, buffers, salts, and additives, i.e. antioxidants, chelating agents, reducing agents and cosolvents, on the stability and the activity of alliinase extracted from garlic. The effects of the storage temperature and relative humidity on the stability of lyophilized alliinase was demonstrated. A combination of the short half-life, high reactivity and non-specificity to particular proteins are reasons most bacteria cannot deal with allicin's mode of action and develop effective defence mechanism, which could be the key to sustainable drug design addressing serious problems with escalating emergence of multidrug-resistant (MDR) bacterial strains.
- MeSH
- antibakteriální látky farmakologie MeSH
- Bacteria účinky léků ultrastruktura MeSH
- biokatalýza účinky léků MeSH
- časové faktory MeSH
- česnek enzymologie MeSH
- chemické jevy * MeSH
- disulfidy chemie metabolismus MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny sulfinové chemie metabolismus MeSH
- lyasy štěpící vazby C-S metabolismus MeSH
- lyofilizace MeSH
- mikrobiální testy citlivosti MeSH
- mikrobiální viabilita účinky léků MeSH
- pufry MeSH
- stabilita enzymů účinky léků MeSH
- stereoizomerie MeSH
- teplota MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diagnostika vředové choroby musí být přesná a založená na endoskopickém vyšetření, u vředové choroby žaludku navíc na bioptickém vyšetření, aby byla odlišena léze benigní od maligní. Vředová choroba je úzce spojena s infekcí H. pylori. Malá skupina nemocných s vředovou chorobou dvanáctníku bez H. pylori (asi 5 - 10 %) tvoří zatím nepřesně definovanou skupinu nemocných. H. pylori se podílí na vzniku gastritidy a bulbitidy, na jejichž bázi vzniká vředová léze. Je-li likvidována infekce H. pylori, dojde k jejímu ústupu a rekurence vředu se sníží na minimum. K průkazu H. pylori slouží invazivní a neinvazivní testy. Z invazivních je důležitá kombinace ureázového testu s histologií, z neinvazivních dechové testy. Léčba směřuje k plnému vymýcení H. pylori z žaludeční sliznice (eradikace), prokázanému za měsíc či déle od ukončení léčby aspoň dvěma metodami. Z léčebných systémů se nejvíce osvědčují trojkombinace s inhibitory protonové pumpy (dvojnásobná terapeutická dávka), klaritromycinem a metronidazolem nebo amoxicilinem. Je-li tato léčba neúspěšná, je možné se pokusit o léčbu čtyřkombinací, kdy k trojkombinaci přidáme jako čtvrtý lék koloidní bizmut subcitrát. Přesná diagnostika vředových lézí a infekce H. pylori se stala základem pro racionální léčbu vředové choroby i prevenci její rekurence.
The diagnosis of peptic ulcer must be precise and based on both endoscopic examination (in the case of gastric ulcer to differentiate between benign or malign ulcers), and on bioptic examination. Peptic ulcer is pathogenetically associated with H. pylori. A small group of patients with duodenal ulcers and without H. pylori or without an other known cause (NSAID, etc.) is a poorly defined sub-group of patients. H. pylori has an important role in the pathogenesis of gastritis and bulbitis. Both states are involved in the pathogenesis of peptic ulcer. If H. pylori is eradicated, inflammatory changes of the gastric and duodenal mucosa recede and the recurrence of peptic ulcer decreases to a minimal size. For estimation of H. pylori, several invasive and non-invasive techniques are used. Among invasive methods most used in peptic ulcers, a combination of the rapid urease test and histology seems to be the most important. Among non-invasive methods, the breath tests are the most reliable. The treatment is focused on the eradication of H. pylori (no H. pylori is found one month or more after completed therapy). Of the eradication regimens, the triple therapy with proton pump inhibitors, claritromycin and metronidazole or amoxicilin are most effective. If this therapy fails, quadrutherapy (triple therapy combined with colloid bismuth subcitrate) may be successful. The precise diagnosis of peptic ulcer and H. pylori infection is a basic prerequisite for rational therapy of peptic ulcer disease and its relapses.
- Klíčová slova
- CONTROLOC (BYK GULDEN, SRN), KLACID (ABBOT), ENTIZOL (POLFA, POLSKO), LOSEC (ASTRA, ŠVÉDSKO), DE-NOL (YAMANOUCHI, NIZOZEMÍ),
- MeSH
- Helicobacter pylori patogenita MeSH
- infekce vyvolané Helicobacter pylori diagnóza etiologie farmakoterapie MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- peptický vřed diagnóza terapie MeSH
- protivředové látky farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
