Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties through Biotage Isolera耐士科技
2015-02-13 10:22
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Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by
three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub lg/mL minimum inhibitory concentrations.
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We herein report several highly active catalyst systems with thiadiazolidine 1-oxides as ligands for palladium in the MizorokieHeck reaction. Excellent yields of stilbenes derived from aryl iodides and bromides have been achieved using as little as 0.00002 mol % catalyst. The ligand/palladiumsystem can be stored as a stock solution open to air at room temperature with no observable loss of activity for a period of several months.
耐士科技作为Biotage中国区总代理,以优质的服务为您提供Biotage全系产品以及相关的技术服务。1、开机前确认自动收集机械手臂下无障碍物,试管高度低于机械手臂收集针
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耐士科技作为Biotage中国区总代理,以优质的服务为您提供Biotage全系产品以及相关的技术服务。
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