452-58-4Relevant articles and documents
Discovery and development of 2-aminobenzimidazoles as potent antimalarials
Avery, Vicky M.,Challis, Matthew P.,Creek, Darren J.,De Paoli, Amanda,Devine, Shane M.,Kigotho, Jomo K.,MacRaild, Christopher A.,Norton, Raymond S.,Scammells, Peter J.,Siddiqui, Ghizal
, (2021/06/03)
The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC50 values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.IIC580Y) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC50 > 50 μM). The most potent molecule, possessing a 4,5-dimethyl substituted phenol (3r) displayed an IC50 value of 6.4 ± 0.5 nM against P. falciparum 3D7, representing a 12-fold increase in activity from the parent molecule. The 2-aminobenzimidazoles containing a N1-substituted phenol represent a new class of molecules that have high potency in vitro against P. falciparum malaria and low cytotoxicity. They possessed attractive pharmaceutical properties, including low molecular weight, high ligand efficiency, high solubility, synthetic tractability and low in vitro clearance in human liver microsomes.
Synthesis method of aminopyridine compounds
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Paragraph 0053-0054, (2020/10/14)
The invention provides a synthesis method of aminopyridine compounds. The synthesis method of the aminopyridine compounds comprises the following steps: under a heating condition, halogenated pyridineorganic matters and an ammoniation reagent are subjected to an ammoniation reaction to obtain an ammoniated product system, wherein in the ammoniation reaction, the temperature of the ammoniation reaction is 200-240 DEG C, and the ammoniation reagent is in a solid state and can be decomposed to generate ammonia gas; and the ammoniated product system is sequentially purified and salified to obtainthe aminopyridine compounds. The synthesis method does not need to add a solvent, so that the yield of three wastes can be greatly reduced; the type of the ammonification reagent and the ammonification reaction temperature are limited during the reaction process, such that the high reaction rate and the high conversion rate can be obtained without the addition of the catalyst, and the purification and salification process after the ammonification reaction is simple and has the good separation effect so as to substantially reduce the production cost and improve the product yield and the product purity. In addition, the synthesis method also has the advantages of good repeatability and the like.
Design and synthesis of potent and orally active GPR4 antagonists with modulatory effects on nociception, inflammation, and angiogenesis
Miltz, Wolfgang,Velcicky, Juraj,Dawson, Janet,Littlewood-Evans, Amanda,Ludwig, Marie-Gabrielle,Seuwen, Klaus,Feifel, Roland,Oberhauser, Berndt,Meyer, Arndt,Gabriel, Daniela,Nash, Mark,Loetscher, Pius
, p. 4512 - 4525 (2017/07/22)
GPR4, a G-protein coupled receptor, functions as a proton sensor being activated by extracellular acidic pH and has been implicated in playing a key role in acidosis associated with a variety of inflammatory conditions. An orally active GPR4 antagonist 39c was developed, starting from a high throughput screening hit 1. The compound shows potent cellular activity and is efficacious in animal models of angiogenesis, inflammation and pain.