Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties
作者： Rakesh , David Bruhn , Dora B. Madhura , Marcus Maddox , Robin B. Lee
DOI: 10.1016/J.BMC.2012.08.023
关键词:
摘要: A series of tetracyclic nitrofuran isoxazoline anti-tuberculosis agents was designed and synthesized to improve the pharmacokinetic properties an initial lead compound, which had potent activity but suffered from poor solubility, high protein binding rapid metabolism. In this study, structural modifications were carried on outer phenyl piperidine rings introduce solubilizing metabolically blocking functional groups. The compounds generated evaluated for their in vitro antitubercular activity, bacterial spectrum permeability, microsomal stability binding. Pharmacokinetic profiles most promising candidates then determined. Compounds with morpholine pyridyl found be series. These retained a narrow antibacterial weak anti-Gram positive no Gram negative as well good against non-replicating Mycobacterium tuberculosis low oxygen model. Overall, addition blocked did solubility decrease designed. However, metabolic generally lower than desired. best three selected vivo testing all showed oral bioavailability, one notable compound showing significantly longer half-life tolerability supporting its further advancement.
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