• MeSH
• bezpečnost MeSH
• hodnocení rizik MeSH
• pracovní expozice MeSH
• thiomočovina škodlivé účinky   MeSH
• vystavení vlivu životního prostředí MeSH

• Konspekt
• Veřejné zdraví a hygiena
• NLK Obory
• chemie, klinická chemie
• environmentální vědy
• NLK Publikační typ
• publikace WHO

• MeSH
• finanční podpora výzkumu jako téma MeSH
• glykokonjugáty MeSH
• myši MeSH
• slezina metabolismus   MeSH
• thiomočovina MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• akridiny chemie   MeSH
• aktivace enzymů účinky léků   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• piperaziny chemie   MeSH
• takrin chemie   MeSH
• thiomočovina chemie   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• hmyz anatomie a histologie   účinky léků   MeSH
• sterilizační prostředky chemické farmakologie   MeSH
• thiomočovina farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A new thiourea ligand (HL), namely N-(4-chlorophenyl)morpholine-4-carbothioamide and its Co(III), Ni(II) and Ag(I) complexes (1a, 1b and 1c) were synthesized and investigated by Fourier-transform infrared, 1H NMR and UV-visible spectroscopies. The compounds HL and 1c were characterized by single-crystal X-ray crystallography revealing the triclinic space group P[Formula: see text] for both compounds. The inhibitory effect of HL ligand, 1a, 1b, and 1c complexes was investigated with in vitro tests on Gram-positive and Gram-negative bacteria. For the 1c complex, the results showed that the coordination of the HL to Ag(I) ion increased its antibacterial effect especially against E. coli. The assays also indicated that for the same bacteria strains, the new complexes showed higher activity than the ligand, with the relative activity 1c > 1b > 1a > HL. Moreover, all samples were more suitable antimicrobial agents against the Gram-negative than those of the Gram-positive bacteria. Eventually, the relationship between the structure and bactericidal activities of these specimens was examined by calculating frontier molecular orbital (HOMO and LUMO) energies using density functional theory method at the 6-31 G*/LANL2DZ level of theory.

• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• gramnegativní bakterie účinky léků   MeSH
• grampozitivní bakterie účinky léků   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• magnetická rezonanční spektroskopie MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• morfoliny chemická syntéza   chemie   farmakologie   MeSH
• spektrofotometrie ultrafialová MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• thioamidy chemická syntéza   chemie   farmakologie   MeSH
• thiomočovina metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH

Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.

• MeSH
• akridiny chemie   MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• buněčné jádro metabolismus   MeSH
• inhibitory angiogeneze chemie   farmakologie   MeSH
• interkalátory chemie   farmakologie   MeSH
• invazivní růst nádoru prevence a kontrola   MeSH
• lidé MeSH
• molekulární mimikry MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze farmakoterapie   MeSH
• thiomočovina chemie   MeSH
• zlato chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34μM and 0.30μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• fenylmočovinové sloučeniny chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• monoaminoxidasa metabolismus   MeSH
• thiomočovina chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A combination of biophysical, biochemical, and computational techniques was used to delineate mechanistic differences between the platinum-acridine hybrid agent [PtCl(en)(L)](NO(3))(2) (complex 1, en = ethane-1,2-diamine, L = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) and a considerably more potent second-generation analogue containing L' = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine (complex 2). Calculations at the density functional theory level provide a rationale for the binding preference of both complexes for guanine-N7 and the relatively high level of adenine adducts observed for compound 1. A significant rate enhancement is observed for binding of the amidine-based complex 2 with DNA compared with the thiourea-based prototype 1. Studies conducted with chemical probes and on the bending and unwinding of model duplex DNA suggest that adducts of complex 2 perturb B-form DNA more severely than complex 1, however, without denaturing the double strand and significantly less than cisplatin. Circular and linear dichroism spectroscopies and viscosity measurements suggest that subtle differences exist between the intercalation modes and adduct geometries of the two complexes. The adducts formed by complex 2 most efficiently inhibit transcription of the damaged DNA by RNA polymerase II. Not only do complexes 1 and 2 cause less distortion to DNA than cisplatin, they also do not compromise the thermodynamic stability of the modified duplex. This leads to a decreased or negligible affinity of HMG domain proteins for the adducts formed by either Pt-acridine complex. In a DNA repair synthesis assay the lesions formed by complex 2 were repaired less efficiently than those formed by complex 1. These significant differences in DNA adduct formation, structure, and recognition between the two acridine complexes and cisplatin help to elucidate why compound 2 is highly active in cisplatin-resistant, repair proficient cancer cell lines.

• MeSH
• adukty DNA chemie   MeSH
• akridiny chemie   metabolismus   farmakologie   MeSH
• amidiny chemie   metabolismus   farmakologie   MeSH
• antitumorózní látky chemie   metabolismus   farmakologie   MeSH
• B-DNA chemie   metabolismus   MeSH
• cisplatina analogy a deriváty   chemie   metabolismus   farmakologie   MeSH
• DNA chemie   metabolismus   MeSH
• genetická transkripce účinky léků   MeSH
• HeLa buňky MeSH
• interkalátory chemie   metabolismus   farmakologie   MeSH
• kinetika MeSH
• konformace nukleové kyseliny účinky léků   MeSH
• lidé MeSH
• oprava DNA účinky léků   MeSH
• organoplatinové sloučeniny chemie   metabolismus   farmakologie   MeSH
• protein - isoformy metabolismus   MeSH
• protein HMGB1 metabolismus   MeSH
• racionální návrh léčiv MeSH
• thiomočovina chemie   metabolismus   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH

BACKGROUND: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. METHODS: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. RESULTS: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. CONCLUSION: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

• MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• kinetika MeSH
• kumariny chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• permeabilita účinky léků   MeSH
• simulace molekulového dockingu MeSH
• takrin chemie   farmakologie   MeSH
• thiomočovina chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• thiokyanatany analogy a deriváty   analýza   MeSH
• thiomočovina analogy a deriváty   analýza   MeSH
• thiosemikarbazony analogy a deriváty   analýza   MeSH