153938-40-0Relevant articles and documents
Combinatorial synthesis and in vitro evaluation of a biaryl hydroxyketone library as antivirulence agents against mrsa
Yu, Guanping,Kuo, David,Shoham, Menachem,Viswanathan, Rajesh
supporting information, p. 85 - 91 (2014/03/21)
Antibiotic resistance coupled with decreased development of new antibiotics necessitates the search for novel antibacterial agents. Antivirulence agents offer an alternative to conventional antibiotics. In this work, we report on a family of small-molecule antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA), the most widespread bacterial pathogen. Structure-activity relationship studies led to the development of a concise synthesis of a 148-member biarylhydroxyketone library. An acylation bond-forming process afforded resorcinols (1) and aryloxy acetonitriles (2) as synthons. A Lewis-acid-activated Friedel-Crafts' acylation step involving a nitrile functionality of 2 by ZnCl2, followed by nucleophilic attack by 1 was executed to obtain biaryl hydroxyketones in excellent yields. A large number of products crystallized. This strategy affords a range of biarylhydroxyketones in a single step. This is the first collective synthetic study documenting access to this class of compounds through a single synthetic operation. In vitro efficacy of compounds in this library was evaluated by a rabbit erythrocyte hemolysis assay. The most efficacious compound, 4f-12, inhibits hemolysis by 98.1 ± 0.1% compared to control in the absence of the compound.
Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives
Hirose, Masaaki,Okaniwa, Masanori,Miyazaki, Tohru,Imada, Takashi,Ohashi, Tomohiro,Tanaka, Yuta,Arita, Takeo,Yabuki, Masato,Kawamoto, Tomohiro,Tsutsumi, Shunichirou,Sumita, Akihiko,Takagi, Terufumi,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
, p. 5600 - 5615 (2012/10/29)
Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.
HETEROCYCLIC COMPOUND AND USE THEREOF
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Page/Page column 101, (2010/06/11)
Disclosed is a heterocyclic compound having a strong Raf inhibitory activity. Specifically disclosed is a compound represented by the formula (I), (II) or (III) below, or a salt thereof. (In the formulae, the symbols are as defined in the description.)
BENZOTHIAZOLE DERIVATIVES AS ANTICANCER AGENTS
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Page/Page column 126-127, (2010/06/20)
Provided is a fused heterocycle derivative showing a strong Raf inhibitory activity. A compound represented by the formula (I) wherein each symbol is as defined in the present specification, or a salt thereof.
Synthesis and activities of new arylsulfonamido thromboxane A2 receptor antagonists
Sartori, E.,Camy, F.,Teulon, J. M.,Caussade, F.,Virone-Oddos, A.,Cloarec, A.
, p. 625 - 632 (2007/10/02)
New benzoic, benzeneacetic and thiazole-4-acetic acids bearing an arylsulfonamido alkyl or alkylhetero side chain were synthesized and tested in vitro for affinity for human platelet thromboxane A2 receptors and inhibition of U46619-induced rat aortic ring contraction.Influence of substitution patterns, chain length and presence of heteroatoms were studied and compounds within a 30 nmol range for inhibition of U46619-induced contractions were found.One of the most potent, 2-thiazole-4-acetic acid (VII-4) was orally active (1 mg/kg), as evidenced by the inhibition of U46619-induced platelet aggregation in guinea pigs, ex vivo. thromboxane A2 / receptor antagonist / platelet aggregation / arylsulfonamido derivative
