6191-99-7Relevant academic research and scientific papers
Two birds with one stone: The detection of nerve agents and AChE activity with an ICT-ESIPT-based fluorescence sensor
Meng, Wenqi,Pei, Zhipeng,Wang, Yurun,Sun, Mingxue,Xu, Qingqiang,Cen, Jinfeng,Guo, Kai,Xiao, Kai,Li, Zhenjiang
, (2021)
Nerve agents are among the world's deadliest poisons, and the target enzyme is acetylcholinesterase (AChE). To better diagnosis nerve agent poisonings, a reliable diagnostic method for both nerve agents and AChE is desirable. Herein, we synthesized a series of fluorescent sensors for both real nerve agents and acetylcholinesterase activity detection. Among these sensors, HBQ-AE exhibited a fast response rate (within 10 s for nerve agent and 8 min for AChE), good sensitivity (the limit of detection is 6 nM and 0.2 U/mL) and a high off/on contrast. To the best of our knowledge, HBQ-AE is the first fluorescence sensor for nerve agents and AChE activity detection. The fluorescent change of HBQ-AE from nonfluorescence to blue fluorescence (nerve agent) or orange fluorescence (AChE) by excitation at 365 nm can be easily observed with the naked eye. HBQ-AE was successfully applied to image nerve agents and AChE activity in living cells. Moreover, HBQ-AE is the vital member to construct a test paper that can be employed to detect and diagnose chemical warfare agents.
New 8-Nitroquinolinone Derivative Displaying Submicromolar in Vitro Activities against Both Trypanosoma brucei and cruzi
Bergé, Justine,Bonduelle, Colin,Boudot, Clotilde,Bourgeade-Delmas, Sandra,Boutet-Robinet, Elisa,Brossas, Jean-Yves,Corvaisier, Sophie,Courtioux, Bertrand,Deraeve, Céline,Destere, Alexandre,Fairlamb, Alan H.,Malzert-Fréon, Aurélie,Mazier, Dominique,Milne, Rachel,Paris, Luc,Pedron, Julien,Pinault, Emilie,Pratviel, Geneviève,Since, Marc,Sournia-Saquet, Alix,Stigliani, Jean-Luc,Tronnet, Antoine,Valentin, Alexis,Verhaeghe, Pierre,Wyllie, Susan
, p. 464 - 472 (2020)
An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = -0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds.
UDP GLYCOSYLTRANSFERASE INHIBITORS AND METHODS OF USE
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Paragraph 1325; 1327, (2020/04/24)
Described herein is a compound of Formula (I), and pharmaceutically acceptable salts thereof. Also described herein are compositions and the use of such compositions in methods of treating a variety of diseases and conditions, in particular Krabbe's Disease (KD) and Metachromatic leukodystrophy (MLD).
REGIO-SELECTIVE SYNTHESIS OF IMIDAZO[1,2-A]PYRIMIDINES
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Paragraph 0067; 0073; 0075, (2020/11/23)
A method of regio-selectively synthesizing an imidazo-pyrimidine compound of formulae (XXa) or (XXb) comprising a step of coupling a first compound of formula XX-P1a or XX-P1b with a second compound of formula XX-P2. This annulation reaction between β-ethoxy acrylamides and phosphorylated aminoimidazoles to furnish imidazo[1,2-a]pyrimidin-amines relies on steering effects from endocyclic and exocyclic phosphorylated aminoimidazoles. The reaction furnishes either 2-amino or 4-amino constitutional isomers of imidazo[1,2-a]pyrimidines with good yields and ranges of 90:10 – 99:1 regio-selectivity. The reaction is useful in the synthesis of various tracer molecules used in the study of neurological conditions such as where R3 and R4 together with the imidazole ring atoms to which they are bonded form a phenyl ring and the products are substituted benzimidazopyrimidines. The reaction can be generalized to form imidazo[1,2-a]pyrimidines substituted at either of their 2- and 4- positions by alkoxy or thioalkyl groups.
Pyrimidine quinoline derivatives, and preparation method and applications thereof
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Paragraph 0159-0163, (2019/10/01)
The invention discloses pyrimidine quinoline derivatives, a prodrug, and preparation method and applications thereof. The structure of the pyrimidine quinoline derivatives is represented by formula I, wherein R1 is used for representing hydrogen, C1-4 alkyl, C1-4 halogenated alkyl, C4-7 heterocyclic aryl, C4-7 substituted heterocyclic aryl, benzyl, or substituted benzyl, glycosyl, and amino acid; R2, R3, R4, and R5 are used for independently representing hydrogen, C1-4 alkyl, C1-4 alkyloxy, hydroxyl, amino, or substituted amino, C1-4 halogenated alkyl or halogen, glycosyl, and amino acid; R6 is used for representing substituted or non-substituted five-membered heterocycle, substituted or non-substituted six-membered heterocycle, substituted or non-substituted C8-12 fused heterocycle. The pyrimidine quinoline derivatives possess excellent inhibition effect on five kinds of cancer cells, the inhibition IC50 value of most compounds is lower than 20M, the IC50 value of a part of the compounds is even lower than 5M, the inhibition effect is extremely obvious, and the compounds can be prepared into anti-tumor drugs for applications.
Synthesis and antiviral evaluation of cyclopentyl nucleoside phosphonates
Wang, Mengmeng,Srivastava, Puneet,Liu, Chao,Snoeck, Robert,Andrei, Graciela,De Jonghe, Steven,Herdewijn, Piet
, p. 616 - 625 (2018/03/21)
The synthesis of both 2?-hydroxy-3?-deoxy and 2?-deoxy-3?-hydroxy cyclopentyl nucleoside phosphonates with the natural nucleobases adenine, thymine, cytosine and guanine from a single precursor has been performed. The guanine containing analogues showed antiviral activity. Especially the 3?-deoxy congener 23 was active, displaying an EC50 of 5.35 μM against TK+ VZV strain and an EC50 of 8.83 μM against TK? VZV strain, besides lacking cytotoxicity. However, the application of phosphonodiamidate prodrug strategy did not lead to a boost in antiviral activity.
HETEROCYCLIC COMPOUNDS USEFUL AS ANTI-BACTERIAL AGENTS AND METHOD FOR PRODUCTION THEREOF
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Paragraph 000209, (2019/01/06)
The present disclosure relates to compounds of Formula I, or their stereoisomers, pharmaceutically acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures, optically active forms and pharmaceutically active derivatives thereof, and pharmaceutical compositions containing them as the active ingredient which can be used as medicaments. The aforementioned substances can also be used in the manufacture of medicaments for treatment, prevention or suppression of diseases, and conditions mediated by microbes. The present disclosure also relates to the synthesis and characterization of aforementioned substances.
INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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, (2018/06/30)
Compounds of formula (I') and methods of their use and preparation, as well as compositions comprising compounds of formula (I').
Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
Igoe, Niall,Bayle, Elliott D.,Tallant, Cynthia,Fedorov, Oleg,Meier, Julia C.,Savitsky, Pavel,Rogers, Catherine,Morias, Yannick,Scholze, Sarah,Boyd, Helen,Cunoosamy, Danen,Andrews, David M.,Cheasty, Anne,Brennan, Paul E.,Müller, Susanne,Knapp, Stefan,Fish, Paul V.
supporting information, p. 6998 - 7011 (2017/09/07)
The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.
High-affinity recognition of the human C-reactive protein independent of phosphocholine
Yang, Jie,Gustavsson, Anna-Lena,Haraldsson, Martin,Karlsson, G?ran,Norberg, Thomas,Baltzer, Lars
supporting information, p. 4644 - 4654 (2017/07/10)
A high-affinity polypeptide conjugate 4-C25L22-DQ, has been developed for the molecular recognition of the human C-reactive protein, CRP, a well-known inflammation biomarker. CRP is one of the most frequently quantified targets in diagnostic applications and a target in drug development. With the exception of antibodies, most molecular constructs take advantage of the known affinity for CRP of phosphocholine that depends on Ca2+ for its ability to bind. 4-C25L22-DQ which is unrelated to phosphocholine binds in the absence of Ca2+ with a dissociation constant of 760 nM, an order of magnitude lower than that of phosphocholine, the KD of which is 5 μM. The small organic molecule 2-oxo-1,2-dihydroquinoline-8-carboxylic acid (DQ) was designed based on the structural similarities between three hits from a set of compounds selected from a building block collection and evaluated with regards to affinity for CRP by NMR spectroscopy. 4-C25L22-DQ was shown in a competition experiment to bind CRP three orders of magnitude more strongly than DQ itself, and in a pull-down experiment 4-C25L22-DQ was shown to extract CRP from human serum. The development of a robust and phosphocholine-independent recognition element provides unprecedented opportunities in bioanalytical applications in vivo and in vitro under conditions where the concentration of Ca2+ ions is low, or where Ca2+ binding agents such as EDTA or heparin are needed to prevent blood coagulation. The identification from a compound library of a small organic molecule and its conjugation to a small set of polypeptides, none of which were previously known to bind CRP, illustrates a convenient and general route to selective high-affinity binders for proteins with dissociation constants in the μM to nM range for which no small molecule ligands are known.
