Pyrazole
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Tento článek představuje výsledky studie zaměřené na syntézu, hodnocení fyzikálně-chemických vlastností, antiradikálové a antimikrobiální aktivity pyrazolových heterocyklických hybridů. Bylo prokázáno, že heterocyklické hybridy nesoucí pyrazol, které obsahují chinazolin, triazolochinazolin nebo triazolové skupiny, jsou dostupné prostřednictvím série reakcí zahrnujících interakci 4-chlorochinazolinu s pyrazolovými hydrazidy, cyklizaci vytvořených produktů na odpovídající triazolochinazolinové deriváty a hydrolytický rozklad elektronově deficitního tricyklického systému. Struktury syntetizovaných sloučenin byly ověřeny komplexem fyzikálně-chemických metod a byly popsány i charakteristické znaky 1 H NMR spektrálních vlastností. Hodnocení biologické aktivity získaných sloučenin odhalilo mírný bakteriostatický účinek proti Pseudomonas aeruginosa a Candida albicans, stejně jako vysokou schopnost některých studovaných heterocyklických hybridů zachytávat radikály.
The paper presents the results of a study devoted to the synthesis, evaluation of physicochemical properties, antiradical, and antimicrobial activity of pyrazole-containing heterocyclic hybrids. It has been shown that pyrazole bearing heterocyclic hybrids that contain quinazoline, triazoloquinazoline or triazole moieties are available via a series of reactions that include the interaction of 4-chloroquinazoline with pyrazole-containing hydrazides, cyclization of formed products into corresponding triazoloquinazolines, and hydrolytic cleavage of the electron-deficient tricyclic system. The structures of synthesized compounds have been verified by a complex of physicochemical methods, and the features of 1H NMR spectral characteristics have been described as well. The evaluation of obtained compounds' biological activity revealed a moderate bacteriostatic effect against Pseudomonas aeruginosa and Candida albicans, as well as high radical scavenging activity of some of the studied heterocyclic hybrids.
- MeSH
- antibakteriální látky farmakologie klasifikace MeSH
- chinazoliny analýza chemie farmakologie MeSH
- heterocyklické sloučeniny * analýza chemie farmakologie MeSH
- objevování léků metody MeSH
- pyrazoly analýza chemie farmakologie MeSH
- triazoly analýza chemie farmakologie MeSH
- volné radikály farmakologie MeSH
- výzkumný projekt MeSH
Reakciou salicylaldehydu (Scl) s príslušnou aminokyselinou a následnou komplexotvomou reakciou vzniknutej Schiffovej zásady s iónmi Cu 2+vo vodno-alkoholovom prostredí boli pripravené akva-(N-salicylidénaminoalkanoáto)mednaté komplexné cheláty zloženia Cu(Scl-DL-Asp(2-))(H2O)2, Ip a Cu(Scl-L-Asn(2-))(H20), In. Monodiazolové komplexy s pyrazolom IIp a IIn (ako monohydrát) a s 3,5-dimetylpyrazolom IIIp a IIIn boli pripravené nahradením molekuly vody príslušným diazolom vo východiskových akvakomplexoch za tých istých reakčných podmienok. Antimikróbna aktivita syntetizovaných komplexov a voľných diazolov bola testovaná bežnou dilučnou mikrometódou voči Staphylococcus aureus, Escherichia coli a Candida albicans. Bola zistená iba významná antistafylokoková aktivita (najvyššia pre komplex IIn; MIC = 39 μg/cm3 ) Všetky cheláty (Ip, n-IIIp,n) bdi účiímejšie (MIC = 39-156 μg/cm3 ) ako sám pyrazol (312 μg/cm3 ) a 3,5-dimetylpyrazol (625 μg/cm3 ). Vzťah medzi koordinačno-chemickými vlastnosťami a biologickým účinkom študovaných komplexov je diskutovaný.
By a reaction of salicylaldehyde (Scl) with the corresponding amino acids and by the next complexation reaction of the formed Schiff bases with Cu 2+ ions in an aqueous-alcoholic medium, aqua(N-salicylideneaminoalkanoato)copper(II) complex chelates of the composition Cu(Scl-DL-Asp(2-)) (H2O)2, Ip and Cu(Scl-L-Asn(2.))(H2O), In were prepared. The monodiazole complexes with pyrazole lip and Iln (as monohydrate) as well as with 3,5-dimethylpyrazole IIIp a IIIn were prepared by replacing the molecule of H2O in the parent aquacomplexes with the diazoles under the same reaction conditions. Using a routine dilution micromethod, the antimicrobial activity of the prepared complexes and free diazoles was tested against Staphylococcus aureus, Escherichia coli and Candida albicans. Qnly a significant antistaphylococcus activity was found (highest for the complex IIn; MIC = 39 μg/cm V All chelates (Ip,n-IIIp,n) were more effective (MIC = 39-156 μg/cm3 ) than both pyrazole (312 μg/cm3 ) and 3,5-dimethylpyra2ole (625 μg/cm3) alone. The relationship between the coordination-chemical properties and the biological effects of the complexes studied is discussed.
Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10-2000 μmol l-1; the kcat values appeared mostly between 0.1 and 1.0 s-1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.
- MeSH
- aldehyddehydrogenasa metabolismus MeSH
- aldehydy chemie metabolismus MeSH
- hrách setý enzymologie MeSH
- imidazoly chemie metabolismus MeSH
- kukuřice setá enzymologie MeSH
- molekulární struktura MeSH
- oxidace-redukce MeSH
- pyrazoly chemie metabolismus MeSH
- Solanum lycopersicum enzymologie MeSH
- Publikační typ
- časopisecké články MeSH
Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 μM. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.
- MeSH
- ATM protein MeSH
- cisplatina farmakologie MeSH
- indoly MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky * farmakologie MeSH
- pyrazoly farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
- MeSH
- antimetabolity diagnostické užití MeSH
- azosloučeniny farmakologie chemická syntéza MeSH
- bromodeoxyuridin diagnostické užití MeSH
- buněčný cyklus účinky léků MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory MeSH
- cyklin-dependentní kinasy antagonisté a inhibitory MeSH
- financování organizované MeSH
- imunoblotting MeSH
- inhibitory enzymů farmakologie chemická syntéza MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- nádorové buněčné linie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- proliferace buněk účinky léků MeSH
- pyrazoly farmakologie chemická syntéza MeSH
- reverzní transkripce účinky léků MeSH
- RNA biosyntéza izolace a purifikace MeSH
- substrátová specifita MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2-CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50 < 20 nm); which can be further optimized to have selectivity over other kinase isoforms.
- MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory proteinkinas chemická syntéza metabolismus MeSH
- lidé MeSH
- protein - isoformy antagonisté a inhibitory metabolismus MeSH
- pyrazoly chemie metabolismus MeSH
- pyrimidiny chemie MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- terciární struktura proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
