14529-12-5Relevant articles and documents
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.
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.
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.
