Evolution of Small Molecule Inhibitors of Mycobacterium tuberculosis Menaquinone Biosynthesis

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-04 DOI:10.1021/acs.jmedchem.4c03156

Pankaj Sharma, Quan Jiang, Shao-Gang Li, Elissa Ocke, Kholiswa Tsotetsi, Paridhi Sukheja, Parul Singh, Shraddha Suryavanshi, Ethan Morrison, Srinivas Thadkapally, Riccardo Russo, Suyapa Penalva-Lopez, Julianna Cangialosi, Vijeta Sharma, Kyla Johnson, Jansy P. Sarathy, Andrew M. Nelson, Steven Park, Matthew D. Zimmerman, David Alland, Pradeep Kumar, Joel S. Freundlich

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Abstract

A dire need exists for novel drugs to treat Mycobacterium tuberculosis infection. In an effort to build on our early efforts targeting the MenG enzyme within the menaquinone biosynthetic pathway, we have pursued the optimization of diaryl amide JSF-2911 to address its poor metabolic stability and modest in vitro potency. A hit evolution campaign focused on modification of the amine substructure within this hit compound, resulting in a range of analogues that have been profiled extensively. Among these derivatives, JSF-4536 and JSF-4898 demonstrated significantly improved biological profiles, notably offering submicromolar MIC values versus M. tuberculosis and promising values characterizing the mouse liver microsome stability, aqueous solubility, and mouse pharmacokinetic profile. JSF-4898 enhanced the efficacy of rifampicin in a subacute model of M. tuberculosis infection in mice. The findings suggest a rationale for the further optimization of MenG inhibitors to provide a novel therapeutic strategy to address M. tuberculosis infection.

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治疗结核分枝杆菌感染急需新型药物。为了在我们早期针对 Menaquinone 生物合成途径中 MenG 酶所做努力的基础上更进一步，我们对二芳基酰胺 JSF-2911 进行了优化，以解决其代谢稳定性差和体外药效不强的问题。我们对该化合物的胺亚结构进行了改造，从而开发出一系列类似物，并对其进行了广泛的研究。在这些衍生物中，JSF-4536 和 JSF-4898 的生物学特性得到了显著改善，尤其是对结核杆菌的 MIC 值达到了亚摩尔级，在小鼠肝脏微粒体稳定性、水溶性和小鼠药代动力学特性方面也取得了可喜的成果。JSF-4898 在小鼠感染结核杆菌的亚急性模型中增强了利福平的疗效。这些发现为进一步优化 MenG 抑制剂提供了理论依据，从而为治疗结核杆菌感染提供了一种新的治疗策略。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.