Bacterial resistance has become a global concern for public health agencies. Various resistance mechanisms found in Staphylococcus aureus strains grant this bacterium resistance to a wide range of antibiotics, contributing to the rise in human mortality worldwide. Resistance mediated by efflux pumps is one of the most prevalent mechanisms in multi-resistant bacteria, which has aroused the interest of several researchers in the search for possible efflux pump inhibitors. In view of the aforementioned considerations, it is important that new strategies, such as the synthesis of chalcones, be made available as a viable strategy in antimicrobial therapy. In this study, the synthesized chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one was tested for its antibacterial activity, focusing on antibiotic modification and the inhibition of the MepA efflux pump present in S. aureus strain K2068. The broth microdilution method, using microdilution plates, was employed in microbiological tests to determine the minimum inhibitory concentration of the chalcone, antibiotics, and ethidium bromide. The results show that while the chalcone did not exhibit direct antibacterial activity, it synergistically enhanced the effects of ciprofloxacin and ethidium bromide, as evidenced by the reduction in MICs. In addition, computer simulations of molecular docking demonstrate that the tested chalcone acts on the same binding site as the efflux pump inhibitor chlorpromazine, interacting with essentially the same residues. These data suggest that the chalcone may act as a MepA inhibitor.
- MeSH
- antibakteriální látky * farmakologie chemie chemická syntéza MeSH
- bakteriální proteiny * metabolismus genetika chemie antagonisté a inhibitory MeSH
- chalkon * farmakologie chemie MeSH
- chalkonoidy * farmakologie chemie MeSH
- lidé MeSH
- membránové transportní proteiny * metabolismus genetika chemie MeSH
- mikrobiální testy citlivosti MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům * metabolismus genetika chemie MeSH
- simulace molekulového dockingu MeSH
- Staphylococcus aureus * účinky léků genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Primární biliární cholangitida (PBC) je chronické, imunologicky podmíněné jaterní onemocnění, které ve svém dlouhodobém průběhu vede k destrukci malých žlučovodů, cholestáze, fibróze a cirhóze jater s jaterním selháním. PBC postihuje ve více než 90 % ženy středního věku, většina pacientů je nyní diagnostikována v asymptomatickém stadiu. Diagnóza onemocnění je obvykle stanovena na základě kombinace laboratorních vyšetření, elevace sérové ALP nad 1,5násobek normy trvající déle než 6 měsíců a přítomnosti AMA protilátek v titru 1: 40 nebo vyšším. Typický histologický nález potvrzuje diagnózu, stadium jaterního onemocnění je však nyní možné určit i pomocí neinvazivních metod. Kyselina ursodeoxycholová je v současné době léčbou první volby, v případě intolerance nebo nedostatečné odpovědi na léčbu je možné zahájit léčbu elafibranorem, duálním agonistou PPAR a/d. Transplantace jater je indikována u pacientů s PBC, kteří dospěli do stadia jaterního selhání i přes podávanou medikamentózní léčbu.
Primary biliary cholangitis (PBC) is a chronic, autoimmune disorder of the liver. In its long-term course, it leads to small bile ducts destruction, cholestasis, liver fibrosis, cirrhosis and chronic liver failure. PBC is much common in women, especially of middle age. Most patients are diagnosed in an asymptomatic stage. The diagnosis is based on the combination of laboratory assessments, alkaline phosphatase elevation of more than 1,5 ULN for more than 6 months, and AMA antibodies in a titre 1: 40 or higher. The typical histological finding confirms the diagnosis, but the stage of liver disease may be determined based on the non-invasive liver stiffness measurement. Ursodeoxycholic acid represents nowadays standard-of-care in PBC patients, followed by elafibranor in intolerant patients or in non-responders. Liver transplantation is indicated in those with liver failure in whom conservative therapy failed.
- Klíčová slova
- Elafibranor,
- MeSH
- biliární cirhóza * diagnóza etiologie farmakoterapie MeSH
- chalkonoidy farmakologie terapeutické užití MeSH
- kyselina ursodeoxycholová farmakologie terapeutické užití MeSH
- lidé MeSH
- PPAR alfa farmakologie terapeutické užití MeSH
- PPAR delta farmakologie terapeutické užití MeSH
- propionáty farmakologie terapeutické užití MeSH
- transplantace jater MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- ABC transportéry * metabolismus chemie genetika MeSH
- akridiny * chemie farmakologie MeSH
- chalkon * farmakologie chemie MeSH
- chalkonoidy * farmakologie chemie MeSH
- chemorezistence účinky léků MeSH
- kolorektální nádory metabolismus farmakoterapie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- P-glykoproteiny metabolismus genetika MeSH
- proliferace buněk účinky léků MeSH
- protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus genetika MeSH
- protinádorové látky * farmakologie chemie MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Gram-positive bacteria are responsible for a wide range of infections in humans. In most Gram-positive bacteria, sortase A plays a significant role in attaching virulence factors to the bacteria's cell wall. These cell surface proteins play a significant role in virulence and pathogenesis. Even though antibiotics are available to treat these infections, there is a continuous search for an alternative strategy due to an increase in antibiotic resistance. Thus, using anti-sortase drugs to combat these bacterial infections may be a promising approach. Here, we describe a method for targeting Gram-positive bacterial infection by combining curcumin and trans-chalcone as sortase A inhibitors. We have used curcumin and trans-chalcone alone and in combination as a sortase A inhibitor. We have seen ~78%, ~43%, and ~94% inhibition when treated with curcumin, trans-chalcone, and a combination of both compounds, respectively. The compounds have also shown a significant effect on biofilm formation, IgG binding, protein A recruitment, and IgG deposition. We discovered that combining curcumin and trans-chalcone is more effective against Gram-positive bacteria than either compound alone. The present work demonstrated that a combination of these natural compounds could be used as an antivirulence therapy against Gram-positive bacterial infection.
- MeSH
- aminoacyltransferasy * antagonisté a inhibitory metabolismus MeSH
- antibakteriální látky * farmakologie chemie MeSH
- bakteriální proteiny * metabolismus antagonisté a inhibitory MeSH
- biofilmy * účinky léků MeSH
- chalkon * farmakologie chemie MeSH
- cysteinové endopeptidasy * metabolismus MeSH
- faktory virulence metabolismus MeSH
- grampozitivní bakteriální infekce farmakoterapie mikrobiologie MeSH
- grampozitivní bakterie účinky léků MeSH
- kurkumin * farmakologie chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- virulence účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
- MeSH
- chalkon chemie farmakologie MeSH
- chalkonoidy chemie farmakologie MeSH
- glutathion-S-transferasa fí * antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů farmakologie chemie MeSH
- kumariny * chemie farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové buněčné linie MeSH
- protinádorové látky farmakologie chemie MeSH
- simulace molekulového dockingu * MeSH
- sulfonamidy * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2'-hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(NN)(μ-L)Cu(NN)](NO3)2⋅nH2O (n = 0-2) (1-5), where NN stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2'-bipyridine, 2), mebpy (5,5'-dimethyl-2,2'-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 ≈ 0.35-7.8 μM. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential. SYNOPSIS: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.
- MeSH
- apoptóza MeSH
- chalkon * farmakologie MeSH
- chalkonoidy * farmakologie MeSH
- komplexní sloučeniny * farmakologie chemie MeSH
- lidé MeSH
- ligandy MeSH
- měď chemie MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * MeSH
- protinádorové látky * farmakologie chemie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8-23 were obtained using the classical base-catalyzed Claisen-Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.
- MeSH
- Chagasova nemoc * farmakoterapie MeSH
- chalkon * farmakologie MeSH
- Leishmania * MeSH
- leishmanióza * farmakoterapie MeSH
- lidé MeSH
- naftaleny terapeutické užití MeSH
- trypanocidální látky * chemie MeSH
- Trypanosoma cruzi * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action.
- MeSH
- antibakteriální látky * chemie farmakologie MeSH
- antiflogistika * chemie farmakologie MeSH
- antioxidancia * chemie farmakologie MeSH
- biologické přípravky * chemie farmakologie MeSH
- buněčné linie MeSH
- chalkonoidy * chemie farmakologie MeSH
- lidé MeSH
- objevování léků MeSH
- protinádorové látky * chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- antidepresiva farmakologie MeSH
- anxiolytika farmakologie MeSH
- Carthamus tinctorius * chemie metabolismus růst a vývoj MeSH
- chalkon analogy a deriváty MeSH
- fytoterapie MeSH
- lidé MeSH
- neuroprotektivní látky farmakologie MeSH
- nootropní látky farmakologie MeSH
- rostlinné extrakty * farmakologie terapeutické užití MeSH
- šalvěj červenokořenná MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 μM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 μM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 μM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 μM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.
- MeSH
- antituberkulotika chemická syntéza chemie farmakologie toxicita MeSH
- buňky 3T3 MeSH
- chalkonoidy chemická syntéza chemie farmakologie toxicita MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemická syntéza chemie farmakologie toxicita MeSH
- screeningové testy protinádorových léčiv MeSH
- sulfonamidy chemická syntéza chemie farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
