2898-08-0Relevant academic research and scientific papers
Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group
Jose, Arathy,Tareque, Raysa Khan,Mortensen, Martin,Legay, Remi,Coles, Simon J.,Tizzard, Graham J.,Greenland, Barnaby W.,Smart, Trevor G.,Bagley, Mark C.,Spencer, John
, (2021)
The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1H-benzo[1,4]diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABAA receptor activation, most likely because of a lost ligand interaction with His102 in the GABAA receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.
TRICYCLIC CRBN LIGANDS AND USES THEREOF
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Paragraph 0776; 0778, (2020/01/24)
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of CRBN, and the treatment of CRBN-mediated disorders.
Structure-Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin
Abdelkafi, Hajer,Michau, Aurélien,Pons, Valérie,Ngadjeua, Flora,Clerget, Alexandra,Ait Ouarab, Lilia,Buisson, David-Alexandre,Montoir, David,Caramelle, Lucie,Gillet, Daniel,Barbier, Julien,Cintrat, Jean-Christophe
, p. 8114 - 8133 (2020/09/21)
High-throughput screening has shown that Retro-1 inhibits ricin and Shiga toxins by diminishing their intracellular trafficking via the retrograde route, from early endosomes to the Golgi apparatus. To improve the activity of Retro-1, a structure-activity relationship (SAR) study was undertaken and yielded an analogue with a roughly 70-fold better half-maximal effective concentration (EC50) against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.
Simple synthetic process of quazepam intermediate
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Paragraph 0015-0017, (2019/05/08)
The invention discloses a simple synthetic process of a quazepam intermediate. 2-aminobenzophenone, triethylamine and DCM are taken and stirred, chloroacetyl chloride is dropped until the reaction iscomplete, liquid separation, extraction and drying are carried out, underpressure distillation is carried out, tert-butyl methyl ether is added, filtered and dried to obtain a first intermediate, thefirst intermediate, aluminium trichloride and dichloromethane are taken and stirred until the reaction is complete; the reaction solution is poured into ice 3N hydrochloric acid and liquid separationis carried out; water phase DCM extraction is carried out once; organic phases are combined and dried with anhydrous sodium sulfate; filtration is carried out, a filtrate is collected, the filtrate, 30% hydrogen peroxide, TBAB and sodium sulfide nonahydrate are stirred and heated until the reaction is complete; filtration, liquid separation and extraction are carried out, and organic phases are combined; the organic phases are washed with saturated brine and dried with anhydrous sodium sulfate; underpressure distillation is carried to remove a solvent, tert-butyl methyl ether and ethyl acetateare added into residues, pulping is carried out at room temperature, and filtration is carried out; and filter cakes are collected and dried with an infrared lamp to obtain the final product with theyield being 78.7% and the purity being 99.2%. The simple synthetic process has the advantages of easily available raw materials, simple and convenient operation and high yield.
Molecular docking, synthesis and CNS activity of some novel 1, 4-Benzodiazepine derivatives
Menghani, Sunil S.,Chikhale, Rupesh,Pant, Amit,Mathew, Bijo,Khedekar, Pramod
, p. 690 - 698 (2017/07/15)
Background: A series of new class of twenty four 1, 4-benzodizepines were designed and by using molecular docking study with GABAA receptor, high scoring fourteen molecules were synthesized from this library. Binding affinity of ligands towards GABAA was evaluated on the basis of dock score and bonding interactions like hydrogen bonds, hydrophobic bonds and pi-stacking. Methods: All compounds were found to possess a good dock score, but varied in the formation of bonding interactions. Methoxy group substituted ligands showed particularly very important role in these interactions. All the synthesized molecules were characterized by IR, 1H-NMR and Mass spectrometric data and investigated for their antianxiety and antiepileptic actions. Conclusion: Compound 3-(3-ethoxy-4-hydroxybenzylidene)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was found to possess very effective in both the activities. All results, docking as well as pharmacological evaluations were compared to diazepam.
Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors
Reddy, D. Rajasekhar,Ballante, Flavio,Zhou, Nancy J.,Marshall, Garland R.
supporting information, p. 531 - 553 (2017/01/24)
A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.
An Atom-Economical Method to Prepare Enantiopure Benzodiazepines with N-Carboxyanhydrides
Fier, Patrick S.,Whittaker, Aaron M.
supporting information, p. 1454 - 1457 (2017/03/23)
The development of a rapid, one-pot synthesis of diazepinones with simple reagents is described. N-Carboxyanhydrides (NCAs) are employed as amino acid building blocks that react with o-ketoanilines sequentially as electrophiles and nucleophiles to form diazepinones with water and carbon dioxide as byproducts. Notably, these reactions enable the coupling of stereodefined amino acid derived NCAs without racemization. This method is demonstrated by an improved synthesis of a key intermediate toward a bromodomain and extra-terminal (BET) bromodomain inihibitor.
Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
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Paragraph 0598, (2017/01/23)
This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
COMPOUNDS WHICH HAVE A PROTECTIVE ACTIVITY WITH RESPECT TO THE ACTION OF TOXINS AND OF VIRUSES WITH AN INTRACELLULAR MODE OF ACTION
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Paragraph 0348; 0349; 0350; 0351, (2016/04/19)
The subject matter of the present invention is novel families of compounds which are aromatic amine, imine, aminoadamantane and benzodiazepine derivatives, medicaments comprising same and the use thereof as inhibitors of the toxic effects of toxins with intracellular activity, such as, for example, ricin, and of viruses that use the internalization pathway for infecting cells.
Antimicrobial benzodiazepine-based short cationic peptidomimetics
Zats, Galina M.,Kovaliov, Marina,Albeck, Amnon,Shatzmiller, Shimon
, p. 512 - 519 (2015/05/27)
Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic 'back', and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 μg/ml against Staphylococcus aureus and 25 μg/ml against Escherichia coli, similar to the well-known antimicrobial peptide MSI-78. In contrast to MSI-78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications.
