The new thiazolidine-2,4-dione-based hybrids with promising antimycobacterial activity: design, synthesis, biological evaluation, and drug interaction analysis

The ever-increasing drug-resistant tuberculosis (TB) has invigorated the focus on the discovery and development of novel therapeutic agents and treatment options. Thiazolidinone-based compounds have shown good antitubercular properties <i>in vitro</i>. Here, we report the design and synthesis of a number of new derivatives inspired by the structure of thiazolidine-2,4-dione (TZD). The TZD-based hybrids with the thiosemicarbazone or the pyridinecarbohydrazone moiety were synthesised and their antimycobacterial activity was investigated against the reference H₃₇Rv and two wild <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) strains. In further studies, a two-drug interaction analysis was also performed for assessing their synergism with the current first-line drugs used for the treatment of TB. It was found that some of the compounds showed high antimycobacterial activity with MICs (0.078–0.283 µM) and a synergistic effect with isoniazid or rifampicin, thereby demonstrating their potential as a promising scaffold for the development of novel coadjuvants for the effective treatment of TB.

日益增长的耐药性结核病（drug-resistant tuberculosis，TB）促使人们将研究重点转向新型治疗药物和方案的发现与开发。噻唑烷酮（thiazolidinone）类化合物已在体外（<i>in vitro</i>）展现出良好的抗结核活性。本文报道了一系列受噻唑烷-2,4-二酮（thiazolidine-2,4-dione，TZD）结构启发的新型衍生物的设计与合成。我们合成了含有缩氨基硫脲（thiosemicarbazone）或吡啶碳酰肼（pyridinecarbohydrazone）基团的TZD基杂合物，并研究了其对参考菌株H₃₇Rv及两株野生型<i>Mycobacterium tuberculosis</i>（<i>Mtb</i>）的抗分枝杆菌活性。进一步研究中，我们还进行了双药相互作用分析，以评估这些化合物与当前一线抗结核药物之间的协同效应。结果发现，部分化合物表现出较高的抗分枝杆菌活性，最低抑菌浓度（minimum inhibitory concentrations，MICs）范围为0.078–0.283 μM，且与异烟肼（isoniazid）或利福平（rifampicin）具有协同作用，这表明它们有望成为开发新型辅助药物以有效治疗结核病的潜在骨架。