Design, Synthesis, and Evaluation of the Antitubercular Activity of 5-Phenyl Substituted-5, 6-dihydropyrido[2, 3-d]pyrimidine-4, 7(3H, 8H)-dione Compounds,Journal of Medicinal Chemistry

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Design, Synthesis, and Evaluation of the Antitubercular Activity of 5-Phenyl Substituted-5, 6-dihydropyrido[2, 3-d]pyrimidine-4, 7(3H, 8H)-dione Compounds
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-21 , DOI: 10.1021/acs.jmedchem.4c00441
Lianqi Sun ₁ , Shibo Kou ₁ , Bin Wang ₂ , Yongjian Wang ₁ , Jianzhou Meng ₁ , Tianfu Liu ₁ , Yuanyuan Ma ₁ , Jianyuan Zhao ₁ , Hong Yi ₁ , Shan Cen ₁ , Yu Lu ₂ , Zhuorong Li ₁

Affiliation

Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 μg/mL]. Chiral resolution was performed on compounds 5b and 5j; the isomers were evaluated for their activity and safety, confirming that the R-isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03–0.06 μg/mL; MDR-Mtb: 0.125–0.06 μg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum. Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.

中文翻译：

5-苯基取代-5, 6-二氢吡啶并[2, 3-d]嘧啶-4, 7(3H, 8H)-二酮化合物的设计、合成和抗结核活性评价

结核病 (TB) 仍然是一项重大的公共卫生挑战，新抗结核药物的研究对于全球消除结核病工作至关重要。在这里，我们报告了一类新型的抗结核药物。特别是，化合物5b和5j表现出最高的活性[最低抑制浓度（MIC）H37Rv：0.16和0.12 μg/mL]。对化合物5b和5j进行手性拆分；对异构体的活性和安全性进行了评估，确认R异构体5bb和5jb显示出显着的抗结核活性（MIC H37Rv：0.03–0.06 μg/mL；MDR- Mtb ：0.125–0.06 μg/mL）和低 hERG毒性。对5bb和5jb 的进一步评估显示出良好的代谢稳定性、良好的动力学参数和口服生物利用度（F：分别为 56.7 和 63.8%）。体内活性评估结果表明， 5bb和5jb对感染海分枝杆菌的斑马鱼幼虫和成年斑马鱼具有保护和治疗作用。基于这些结果，化合物5bb和5jb被认为是进一步深入研究的有希望的候选者。

更新日期：2024-08-21

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