National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei, 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei, 430070, China.
Eur J Med Chem. 2021 Nov 5;223:113657. doi: 10.1016/j.ejmech.2021.113657. Epub 2021 Jun 17.
As a continuation of our research on antimycobacterial agents, a series of novel quinoxaline-1,4-di-N-oxides (QdNOs) containing various nitrogenous heterocyclic moieties at the R position were designed and synthesized. Antimycobacterial activities, as well as the cytotoxic effects, of the compounds were assayed. Four compounds (6b, 6f, 6n, and 6o), characterized by 2-carboxylate ethyl or benzyl ester, 6-imidazolyl or 1,2,4-triazolyl, and a 7-fluorine group, exhibited the most potent antimycobacterial activity against M.tb strain H37Rv (MIC ≤ 0.25 μg/mL) with low toxicity in VERO cells (SI = 169.3-412.1). Compound 6o also exhibited excellent antimycobacterial activity in an M.tb-infected macrophage model and was selected for further exploration of the mode of antimycobacterial action of QdNOs. The results showed that compound 6o was capable of disrupting membrane integrity and disturbing energy homeostasis in M.tb. Furthermore, compound 6o noticeably increased cellular ROS levels and, subsequently, induced autophagy in M.tb-infected macrophages, possibly indicating the pathways of QdNOs-mediated inhibition of intracellular M.tb replication. The in vivo pharmacokinetic (PK) profiles indicated that compounds 6o was acceptably safe and possesses favorable PK properties. Altogether, these findings suggest that compound 6o is a promising antimycobacterial candidate for further research.
作为我们对抗结核药物研究的延续，我们设计并合成了一系列新型的含有各种含氮杂环基团的喹喔啉-1,4-二-N-氧化物（QdNOs），位于 R 位。我们对化合物的抗结核活性和细胞毒性进行了测定。四个化合物（6b、6f、6n 和 6o），其特点是 2-羧酸乙酯或苄酯、6-咪唑基或 1,2,4-三唑基和 7-氟基团，对结核分枝杆菌 H37Rv 菌株表现出最强的抗结核活性（MIC≤0.25μg/mL），在 VERO 细胞中毒性低（SI=169.3-412.1）。化合物 6o 在结核分枝杆菌感染的巨噬细胞模型中也表现出优异的抗结核活性，因此被选为进一步探索 QdNOs 抗结核作用模式的候选化合物。结果表明，化合物 6o 能够破坏结核分枝杆菌的膜完整性并扰乱其能量稳态。此外，化合物 6o 显著增加了结核分枝杆菌感染的巨噬细胞中的细胞 ROS 水平，随后诱导自噬，这可能表明 QdNOs 介导的抑制细胞内结核分枝杆菌复制的途径。体内药代动力学（PK）特征表明，化合物 6o 具有可接受的安全性和良好的 PK 特性。总的来说，这些发现表明化合物 6o 是一种很有前途的抗结核候选药物，值得进一步研究。
