14529-12-5Relevant academic research and scientific papers
Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase
Andryianau, Gleb,Bartoszewicz, Agnieszka,Czestkowski, Wojciech,Dymek, Barbara,Dzwonek, Karolina,Golab, Jakub,Golebiowski, Adam,Gruza, Mariusz,Koralewski, Robert,Kowalski, Michal,Matyszewski, Krzysztof,Mazur, Marzena,Niedziejko, Piotr,Olczak, Jacek,Olejniczak, Sylwia,Piotrowicz, Michal C.,Pluta, Elzbieta,Rajkiewicz, Adam A.,Rymaszewska, Aleksandra,Salamon, Magdalena,Sklepkiewicz, Piotr L.,Stefaniak, Filip,Welzer, Mikolaj,Zagozdzon, Agnieszka
, p. 1228 - 1235 (2020/07/03)
Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.
Palladium-Catalyzed Multistep Tandem Carbonylation/N-Dealkylation/Carbonylation Reaction: Access to Isatoic Anhydrides
Wang, Shoucai,Li, Xuan,Zang, Jiawang,Liu, Meichen,Zhang, Siyu,Jiang, Guangbin,Ji, Fanghua
, p. 2672 - 2679 (2020/02/04)
A novel and efficient synthesis of isatoic anhydride derivatives was developed via palladium-catalyzed multistep tandem carbonylation/N-dealkylation/carbonylation reaction with alkyl as the leaving group and tertiary anilines as nitrogen nucleophiles. This approach features good functional group compatibility and readily available starting materials. Furthermore, it provided a convenient approach for the synthesis of biologically and medicinally useful evodiamine.
Synthesis and antimicrobial activity of novel 4-Hydroxy-2-quinolone analogs
Khamkhenshorngphanuch, Thitiphong,Kulkraisri, Kittipat,Janjamratsaeng, Alongkorn,Plabutong, Napasawan,Thammahong, Arsa,Manadee, Kanitta,Na Pombejra, Sarisa,Khotavivattana, Tanatorn
, (2020/07/30)
Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC50) = 1.05 μg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment.
Unsymmetrically substituted dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dione—A convenient scaffold for bioactive molecule design
Bieszczad, Bartosz,Garbicz, Damian,Trzybiński, Damian,Mielecki, Damian,Wo?niak, Krzysztof,Grzesiuk, El?bieta,Mieczkowski, Adam
, (2020/02/22)
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.
Carbene-Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones
Lee, Ansoo,Zhu, Joshua L.,Feoktistova, Taisiia,Brueckner, Alexander C.,Cheong, Paul H.-Y.,Scheidt, Karl A.
, p. 5941 - 5945 (2019/04/03)
A direct decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza-o-QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis–Ferrier rearrangement sequence. Complementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction
Wang, Zi-Xuan,Xiang, Jia-Chen,Wang, Miao,Ma, Jin-Tian,Wu, Yan-Dong,Wu, An-Xin
supporting information, p. 6380 - 6383 (2018/10/20)
The one-pot total synthesis of evodiamine and its analogues is achieved using a three-component reaction. Through continuous biscyclization, various readily available substrates with good functional group tolerance were easily incorporated into biologically active quinazolinocarboline backbones. The use of triethoxymethane as a cosolvent was crucial for this quick and straightforward transformation.
SUBSTITUTED AMINO TRIAZOLES USEFUL AS HUMAN CHITINASE INHIBITORS
-
, (2017/03/21)
Disclosed are amino triazole compounds substituted with a piperidinyl ring that is itself substituted with a heterocyclic ring. These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
Synthesis method of constructing isatoic anhydride and isatoic anhydride derivative by one step by utilizing carbonylation reaction
-
Paragraph 0082; 0083, (2017/11/16)
The invention relates to a method of constructing isatoic anhydride and an isatoic anhydride derivative by one step by utilizing a carbonylation reaction. The method comprises the steps of adding N,N-dialkyl arylamine, a metal palladium catalyst and copper salt as an oxidant and a solvent to a reaction vessel, sleeving a balloon filled with carbon monoxide and oxygen on a reactor, performing a stirring reaction for 1-10h at 40-150 DEG C, performing cooling to a room temperature after reaction completion, dismounting the balloon, filtering a reaction liquid, performing reduced pressure evaporation to remove the solvent to obtain a crude product, and performing column chromatography purification to obtain isatoic anhydride and the isatoic anhydride derivative. The synthesis method of constructing isatoic anhydride and the isatoic anhydride derivative by the one step by utilizing the carbonylation reaction has the characteristics that operation is concise, raw materials are easy to obtain, the functional group tolerance is good, and a yield is excellent; and the method has an important research value on synthesis and preparation of isatoic anhydride and the isatoic anhydride derivative.
Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases
Palomo, Valle,Perez, Daniel I.,Roca, Carlos,Anderson, Cara,Rodríguez-Muela, Natalia,Perez, Concepción,Morales-Garcia, Jose A.,Reyes, Julio A.,Campillo, Nuria E.,Perez-Castillo, Ana M.,Rubin, Lee L.,Timchenko, Lubov,Gil, Carmen,Martinez, Ana
, p. 4983 - 5001 (2017/06/28)
Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-Activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects.
HETEROCYCLIC GSK-3 ALLOSTERIC MODULATORS
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Paragraph 0069; 0082; 0083, (2014/09/03)
The invention relates to heterocyclic derivatives of substituted quinolines as allosteric inhibitors of the glycogen synthase kinase 3 (GSK-3) enzyme. Thus, said compounds can be used in the production of a drug for the treatment and/or prevention of diseases in which GSK-3 is involved, such as: neurodegenerative diseases, inflammatory diseases, cancer and diabetes, as well as to promote a plurality of regenerative processes..
