6313-39-9Relevant articles and documents
1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation
Venter, Jana,Perez, Concepción,van Otterlo, Willem A.L.,Martínez, Ana,Blackie, Margaret A.L.
, p. 1597 - 1600 (2019/05/02)
Glycogen synthase kinase 3 (GSK-3)has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 μM)and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 μM)displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ± 0.043)in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.
Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
, p. 4906 - 4916 (2007/10/03)
Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
Structure-Based Inhibitors of Influenza Virus Salidase. A Benzoic Acid Lead with Novel Interaction
Singh, Sangetta,Jedrzejas, Marek J.,Air, Gillian M.,Luo, Ming,Laver, W. Graeme,Brouillette, Wayne
, p. 3217 - 3225 (2007/10/03)
Influenza virus sialidase is a surface enzyme that is essential for infection of the virus.The catalytic site is highly conserved among all known influenza variants, suggesting that this protein is a suitable target for drug intervention.The most potent known inhibitors are analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), particulary the 4-guanidino derivative (4-guanidino-Neu5Ac2en).We utilized the benzene ring of 4-(N-acetylamino)benzoic acids as a cyclic template to substitute for the dihydropyran ring of Neu5Ac2en.In this study several 3-(N-acylamino) derivatives were prepared as potential replacements for the glycerol side chain of Neu5Ac2en, and some were found to interact with the same binding subsite of sialidase.Of greater significance was the observation that the 3-guanidinobenzoic acid derivative (equivalent to the 4-guanidino grouping of 4-guanidino-Neu5Ac2en), the most potent benzoic acid inhibitor of influenza sialidase thus far identified (IC50 = 10 μM), occupied the glycerol-binding subsite on sialidase as opposed to the guanidino-binding subsite.This benzoic acid derivative thus provides a new compound that interacts in a novel manner with the catalytic site of influenza sialidase.
