A series of thiazolidinediones (TZDs) were synthesized and screened for their effect on the mitochondrial respiration as well as on several mitochondrial respiratory system components of Drosophila melanogaster. Substituted and non-substituted 5-benzylidene and 5-benzylthiazolidine-2,4-diones were investigated. The effect of a substitution in position 3, at the nitrogen atom, of the thiozolidine heterocycle was also investigated. The designed TZDs were compared to UK5099, the most potent mitochondrial pyruvate carrier (MPC) inhibitor, in in vitro and in vivo tests. Compared to 5-benzylthiazolidine-2,4-diones 6–7 and 3-benzylthiazolidine-2,4-dione 8, 5-benzylidenethiazolidine-2,4-diones 2–5 showed more inhibitory capacity on mitochondrial respiration. 5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (3) and 5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (5) were among the best compounds that compared well with UK5099.

Additionally, TZDs 3 and 5, showed no effects on the non-coupled respiration and weak effects on pathways using substrates such as proline, succinate, and G3P. 5-Benzylidenethiazolidine-2,4-dione 3 showed a positive effect on survival and lifespan when added to Drosophila standard and high fat diet. Interestingly, analog 3 completely reversed the effects of high fat diet on Drosophila longevity and induced metabolic changes which suggests an in vivo inhibition of MPC at the mitochondrial level.

合成了一系列噻唑烷二酮 (TZD)，并筛选了它们对黑腹果蝇线粒体呼吸以及几种线粒体呼吸系统成分的影响。研究了取代和未取代的 5-亚苄基和 5-苄基噻唑烷-2,4-二酮。还研究了噻唑烷杂环的 3 位氮原子取代的影响。在体外和体内将设计的 TZD 与最有效的线粒体丙酮酸载体 (MPC) 抑制剂 UK5099 进行比较测试。与 5-benzylthiazolidine-2,4-diones 6-7 和 3-benzylthiazolidine-2,4-dione 8 相比，5-benzylidenethiazolidine-2,4-diones 2-5 对线粒体呼吸的抑制能力更强。5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (3) 和 5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (5) 是与 UK5099 相比表现最好的化合物。

此外，TZDs 3 和 5 对使用脯氨酸、琥珀酸和 G3P 等底物的非耦合呼吸没有影响，而对途径的影响较弱。当添加到果蝇标准和高脂肪饮食中时，5-Benzylidenethiazolidine-2,4-dione 3 显示出对生存和寿命的积极影响。有趣的是，类似物 3 完全逆转了高脂肪饮食对果蝇寿命的影响并诱导了代谢变化，这表明MPC 在线粒体水平的体内抑制。