基于药物化学和代谢组学见解的噻吩并嘧啶类抗结核药物的研发进展
Evolution of a thienopyrimidine antitubercular relying on medicinal chemistry and metabolomics insights.
作者信息
Li Shao-Gang, Vilchèze Catherine, Chakraborty Sumit, Wang Xin, Kim Hiyun, Anisetti Monica, Ekins Sean, Rhee Kyu Y, Jacobs William R, Freundlich Joel S
机构信息
Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, Rutgers University-New Jersey Medical School, Newark, NJ, USA.
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
出版信息
Tetrahedron Lett. 2015 Jun 3;56(23):3246-3250. doi: 10.1016/j.tetlet.2015.02.129.
Abstract
The metabolic instability of an antitubercular small molecule CD117 was addressed through iterative alteration of a key sulfide substituent and interrogation of the effect on growth inhibition of cultured . This process was informed by studies of the intramycobacterial metabolism of CD117 and its inactive carboxylic acid derivative. Isoxazole and thiazole demonstrated significant gains in mouse liver microsomal stability with slight losses in whole-cell activity. This work illustrates the challenges of antitubercular hit evolution, requiring a balance of chemical and biological insights.
摘要
通过对一种关键硫化物取代基进行迭代改变，并探究其对培养物生长抑制的影响，解决了抗结核小分子CD117的代谢不稳定性问题。这一过程是基于对CD117及其无活性羧酸衍生物的分枝杆菌内代谢的研究。异恶唑和噻唑在小鼠肝微粒体稳定性方面有显著提高，但全细胞活性略有损失。这项工作说明了抗结核活性分子优化过程中的挑战，需要在化学和生物学见解之间取得平衡。
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