A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 μM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• cholinergní látky chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• proteinové agregáty účinky léků   MeSH
• takrin 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
• práce podpořená grantem MeSH

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

• MeSH
• adenosinmonofosfát analogy a deriváty   farmakologie   MeSH
• alanin analogy a deriváty   farmakologie   MeSH
• antivirové látky farmakologie   MeSH
• benzothiazoly farmakologie   MeSH
• buněčné linie MeSH
• inhibitory enzymů farmakologie   MeSH
• koronavirová RNA-replikasa antagonisté a inhibitory   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• replikace viru účinky léků   MeSH
• SARS-CoV-2 účinky léků   enzymologie   fyziologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.

• MeSH
• antitumorózní látky chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• estery kyseliny sírové metabolismus   MeSH
• glykosaminoglykany metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• indoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• pyridinové sloučeniny chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem 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

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• močovina analogy a deriváty   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, (1)H, (13)C, (19)F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• benzothiazoly chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• Jurkat buňky MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• simulace molekulového dockingu * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2-aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS(+) scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono-fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis.

• MeSH
• antioxidancia chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• benzothiazoly chemická syntéza   chemie   farmakologie   MeSH
• buňky MDCK MeSH
• flavonoidy chemická syntéza   chemie   farmakologie   MeSH
• HeLa buňky MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• preklinické hodnocení léčiv MeSH
• psi MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• Vizamyl, flutemetamol,
• MeSH
• alergie * MeSH
• Alzheimerova nemoc * diagnóza   farmakoterapie   MeSH
• amyloidní beta-protein * diagnostické užití   MeSH
• aniliny * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• benzothiazoly * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• nežádoucí účinky léčiv * MeSH
• pozitronová emisní tomografie * využití   MeSH
• radiofarmaka * diagnostické užití   MeSH

Protein p53 plays an essential role in the induction of apoptosis by ionizing radiation in haemopoietic cells, the damage of which is the main reason for the development of bone marrow post-irradiation syndrome. p53 activation leads to an increase in the Bcl-2 family pro-apoptotic protein PUMA level. PUMA inhibits all the five anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-XL, Bcl-W and A1) and directly triggers apoptosis mediated by pro-apoptotic proteins Bax/Bak. In proliferating cells, knockout of p53 inhibits apoptosis on the one hand, but on the other disables the cellular division arrest moderated by p21Cip1/Waf1. The radioprotective effect of p53 inhibitor pifithrin was obvious at radiation doses causing the bone marrow syndrome. Knockout of PUMA also exerts its radioprotective effect through blocking the apoptosis induction, but the arrest of cells in the cell cycle through p21 induction is not abolished. PUMA -/- mice are radioresistant in terms of the development of post-irradiation syndrome after all radiation doses. Small molecules are being searched for that could prevent binding of PUMA with Bcl-2 family anti-apoptotic proteins. This would result in apoptosis inhibition and radioprotective or mitigating effects of these inhibitors.

• MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly farmakologie   MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• myši MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• proteiny regulující apoptózu genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• toluen analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

In this study, a series of N-substituted 2-aminobenzothiazoles was prepared according to a recently developed method. Twelve compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the discussed compounds was also performed against fungal, bacterial and mycobacterial species. The biological activities of some compounds were comparable or higher than the standards phenoxymethylpenicillin or pyrazinamide. The most effective compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. For all compounds, the structure-activity relationships are discussed.

• MeSH
• antifungální látky metabolismus   farmakologie   MeSH
• antiinfekční látky chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• benzothiazoly chemická syntéza   chemie   farmakologie   MeSH
• chloroplasty účinky léků   MeSH
• herbicidy chemická syntéza   chemie   farmakologie   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• nádorové buněčné linie MeSH
• Spinacia oleracea MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH