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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs.
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Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs.

机译：新型甲氟喹-异恶唑羧酸酯的前药合成与抗结核活性。

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摘要

5-(2,8-Bis(trifluoromethyl)quinolin-4-yloxymethyl)isoxazole-3-carboxylic acid ethyl ester (compound 3) was reported to have excellent antituberculosis activity against both replicating and non-replicating Mycobacterium tuberculosis, with a minimum inhibitory concentration (MIC) of 0.9 microM and 12.2 microM, respectively. In this study, the antituberculosis activity of compound 3 was further investigated. Its activity appeared to be very specific for organisms of the M. tuberculosis complex and it effected significant reductions of bacterial numbers in infected macrophages with an EC(90) of 4.1 microM. More importantly, the increased in vitro antituberculosis activity of the corresponding acid (compound 4) at pH 6.0 suggested that it may be active in vivo in an acidic environment produced as a consequence of inflammation in the lungs of TB patients. The fact that various ester bioisosteres of compound 3 lost anti-TB activity further suggested that the ester compound 3 may function as a prodrug. The detailed structure-activity relationships (SARs) from this study should facilitate our ultimate goal of improving the anti-TB potency of this isoxazole ester series.
机译：据报道，5-（2,8-双（三氟甲基）喹啉-4-基氧基甲基）异恶唑-3-羧酸乙酯（化合物3）对复制型和非复制型结核分枝杆菌均​​具有优异的抗结核活性，且抑制最小浓度（MIC）分别为0.9 microM和12.2 microM。在这项研究中，进一步研究了化合物3的抗结核活性。它的活性似乎对结核分枝杆菌复杂的生物非常有特异性，并且以4.1 microM的EC（90）显着降低了感染巨噬细胞中细菌的数量。更重要的是，相应酸（化合物4）在pH 6.0时具有更高的体外抗结核活性，这表明它在由结核病患者肺部炎症引起的酸性环境中具有体内活性。化合物3的各种酯生物等排体失去抗TB活性的事实进一步表明，酯化合物3可以用作前药。这项研究的详细构效关系（SARs）应该有助于我们提高该异恶唑酯系列抗结核药效价的最终目标。

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