The Graduate School, University of Santo Tomas, España Blvd., Manila 1015, Philippines.
Laboratory for Organic Reactivity, Discovery and Synthesis (Rm. 410), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espana Blvd., Manila 1015, Philippines.
Int J Mol Sci. 2023 Jul 19;24(14):11632. doi: 10.3390/ijms241411632.
New antitubercular agents with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new arylated quinoline carboxylic acids (QCAs) having activity against replicating and non-replicating (), the causative agent of TB. Thus, the synthesis, characterization, and in vitro screening (MABA and LORA) of 48 QCAs modified with alkyl, aryl, alkoxy, halogens, and nitro groups in the quinoline ring led to the discovery of two QCA derivatives, and adorned with C-2 2-(naphthalen-2-yl)/C-6 1-butyl and C-2 22-(phenanthren-3-yl)/C-6 isopropyl, respectively, as the best inhibitors. DNA gyrase inhibition was shown to be exhibited by both, with QCA illustrating better activity up to a 1 μM test concentration. Finally, a docking model for both compounds with DNA gyrase was developed, and it showed a good correlation with in vitro results.
新的抗结核药物，无论是具有新作用模式还是新抑制模式的药物，都迫切需要克服耐药性结核病（TB）的威胁。本研究对具有抗复制和非复制活性的新型芳基喹啉羧酸（QCA）进行了分析，（）是 TB 的病原体。因此，对喹啉环中带有烷基、芳基、烷氧基、卤素和硝基的 48 种 QCA 进行了合成、表征和体外筛选（MABA 和 LORA），发现了两种带有 C-2 2-（萘-2-基）/C-6 1-丁基和 C-2 22-（菲-3-基）/C-6 异丙基的 QCA 衍生物，分别为最佳抑制剂。这两种化合物都显示出 DNA 拓扑异构酶抑制作用，其中 QCA 在高达 1 μM 的测试浓度下表现出更好的活性。最后，为两种化合物与 DNA 拓扑异构酶建立了对接模型，结果与体外结果具有良好的相关性。
