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
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
- antitumorózní látky * farmakologie chemie 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
- 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
- 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
- Klíčová slova
- Cyclo3Fort,
- MeSH
- chalkon terapeutické užití MeSH
- chronická nemoc terapie MeSH
- fytoterapie MeSH
- hesperidin terapeutické užití MeSH
- kompresní obvazy MeSH
- kyselina askorbová terapeutické užití MeSH
- lidé MeSH
- rostlinné extrakty terapeutické užití MeSH
- Ruscus chemie MeSH
- skleroterapie MeSH
- žilní insuficience * farmakoterapie MeSH
- Check Tag
- lidé MeSH
Chalcones, i.e., compounds with the chemical pattern of 1,3-diphenylprop-2-en-1-ones, exert a wide range of bio-activities, e.g., antioxidant, anti-inflammatory, anticancer, anti-infective etc. Our research group has been focused on pyrazine analogues of chalcones; several series have been synthesized and tested in vitro on antifungal and antimycobacterial activity. The highest potency was exhibited by derivatives with electron withdrawing groups (EWG) in positions 2 and 4 of the ring B. As halogens also have electron withdrawing properties, novel halogenated derivatives were prepared by Claisen-Schmidt condensation. All compounds were submitted for evaluation of their antifungal and antibacterial activity, including their antimycobacterial effect. In the antifungal assay against eight strains of selected fungi, growth inhibition of Candida glabrata and Trichophyton interdigitale (formerly T. mentagrophytes) was shown by non-alkylated derivatives with 2-bromo or 2-chloro substitution. In the panel of selected bacteria, 2-chloro derivatives showed the highest inhibitory effect on Staphylococcus sp. In addition, all products were also screened for their antimycobacterial activity against Mycobacterium tuberculosis H37RV My 331/88, M. kansasii My 235/80, M. avium 152/80 and M. smegmatis CCM 4622. Some of the examined compounds, inhibited growth of M. kansasii and M. smegmatis with minimum inhibitory concentrations (MICs) comparable with those of isoniazid.
- MeSH
- antiinfekční látky * chemická syntéza chemie farmakologie MeSH
- Candida glabrata růst a vývoj MeSH
- chalkon * chemická syntéza chemie farmakologie MeSH
- halogenované uhlovodíky * chemická syntéza chemie farmakologie MeSH
- Mycobacterium růst a vývoj MeSH
- pyraziny * chemická syntéza chemie farmakologie MeSH
- Trichophyton růst a vývoj MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- analýza buněčné migrace metody využití MeSH
- antitumorózní látky * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- biomedicínský výzkum MeSH
- chalkon analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- cytotoxické testy imunologické metody využití MeSH
- endoteliální buňky pupečníkové žíly (lidské) * cytologie enzymologie MeSH
- fotochemoterapie metody využití MeSH
- indikátory a reagencie MeSH
- inhibitory angiogeneze * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- perylen analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- chalkon farmakologie toxicita MeSH
- epitelové buňky metabolismus účinky léků MeSH
- játra účinky léků ultrastruktura MeSH
- karcinogeny metabolismus toxicita MeSH
- krysa rodu rattus MeSH
- mezibuněčná komunikace fyziologie účinky léků MeSH
- peroxidace lipidů účinky záření MeSH
- systém (enzymů) cytochromů P-450 antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
