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
- antitumorózní látky * farmakologie chemie 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
- 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
In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important clinical conditions in humans. Radioactivity-based assay, spectrophotometric-based assay, and an Electrospray Ionization-Mass Spectrometry-based method were employed to ascertain the inhibitory actions of pGlu against PDE5A1, ACE, and urease, respectively. The results unveiled that pGlu potently suppressed the activity of PDE5A1 (half-maximal inhibitory concentration; IC50 = 5.23 µM) compared with that of standard drug sildenafil citrate (IC50 = 7.14 µM). Moreover, pGlu at a concentration of 20 µg/mL was found to efficiently inhibit human ACE with 98.2% inhibition compared with that of standard captopril (99.6%; 20 µg/mL). The urease-catalyzed reaction was also remarkably inactivated by pGlu and standard acetohydroxamic acid with IC50 values of 1.8 and 3.9 µM, respectively. Remarkably, the outcome of in vitro cytotoxicity assay did not reveal any significant cytotoxic properties of pGlu against human cervical carcinoma cells and normal human fetal lung fibroblast cells. In addition to in vitro assays, molecular docking analyses were performed to corroborate the outcomes of in vitro results with predicted structure-activity relationships. In conclusion, pGlu could be presented as a natural and multifunctional agent with promising applications in the treatment of some ailments connected with the above-mentioned anti-enzymatic properties.
- MeSH
- angiotensin konvertující enzym chemie genetika metabolismus MeSH
- buněčné linie MeSH
- cyklické nukleotidfosfodiesterasy, typ 5 chemie genetika metabolismus MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- inhibiční koncentrace 50 MeSH
- kaptopril chemie metabolismus MeSH
- kyselina pyrrolidonkarboxylová chemie metabolismus toxicita MeSH
- kyseliny hydroxamové antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- rekombinantní proteiny biosyntéza chemie izolace a purifikace MeSH
- sildenafil citrát chemie metabolismus MeSH
- simulace molekulového dockingu MeSH
- spektrofotometrie MeSH
- terciární struktura proteinů MeSH
- ureasa antagonisté a inhibitory 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
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
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
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 antiurease activity of the aqueous extracts of 42 plants growing in the Czech Republic was investigated. A phenol-hypochlorite reaction was used for the determination of ammonia produced by urease. The inhibitory activity of the extracts at a concentration of 0.2 mg/mL varied from 17.8% to 80.0%. Extracts from six Potentilla species expressed inhibitory activity against jack bean urease. They were further investigated for their phenolic constituents and the major compounds were subjected to molecular docking. The results revealed that both jack bean urease and Helicobacter pylori urease were inhibited by quercetin-3-O-β-D-galactopyranoside-6″-gallate (1), myricetin-3-O-β-D-glucuronide (2), tiliroside (3) and B-type procyanidin (4). The antiurease activity of the investigated Potentilla species is probably due to the presence of complex phenolic constituents such as flavonoid glycosides and catechin dimers.
- MeSH
- algoritmy MeSH
- Canavalia enzymologie MeSH
- fenoly chemie izolace a purifikace farmakologie MeSH
- flavonoidy chemie izolace a purifikace farmakologie MeSH
- galaktosidy chemie izolace a purifikace farmakologie MeSH
- Helicobacter pylori účinky léků MeSH
- infekce vyvolané Helicobacter pylori farmakoterapie MeSH
- léčivé rostliny chemie MeSH
- Potentilla chemie MeSH
- quercetin analogy a deriváty MeSH
- ureasa antagonisté a inhibitory MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
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
- MeSH
- sinice enzymologie MeSH
- ureasa analýza antagonisté a inhibitory izolace a purifikace MeSH
- Publikační typ
- srovnávací studie MeSH
