In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis,ACS Omega

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In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis
ACS Omega ( IF 3.7 ) Pub Date : 2017-09-18 00:00:00 , DOI: 10.1021/acsomega.7b00892
Joshua Odingo ₁ , Mai A. Bailey ₁ , Megan Files ₁ , Julie V. Early ₁ , Torey Alling ₁ , Devon Dennison ₁ , Julie Bowman ₁ , Suryakanta Dalai ₂ , Naresh Kumar ₂ , Jeffrey Cramer ₃ , Thierry Masquelin ₃ , Philip A. Hipskind ₃ , Tanya Parish ₁

Affiliation

Nitazoxanide has antiparasitic and antibiotic activities including activity against Mycobacterium tuberculosis. We prepared and evaluated a set of its analogues to determine the structure–activity relationship, and identified several amide- and urea-based analogues with low micromolar activity against M. tuberculosis in vitro. Pharmacokinetics in the rat suggested a path forward to obtain bioavailable compounds. The series had a good microbiological profile with bactericidal activity in vitro against replicating and nonreplicating M. tuberculosis. Analogues had limited activity against other Gram-positive bacteria but no activity against Gram-negative bacteria. Our studies identified the key liability in this series as cytotoxicity. Future work concentrating on identifying the target(s) could assist in removing activity against eukaryotic cells.

中文翻译：

新型抗硝唑尼特衍生物对结核分枝杆菌的体外评价

硝唑尼特具有抗寄生虫和抗生素活性，包括抗结核分枝杆菌的活性。我们准备并评估了一组类似物，以确定其结构与活性之间的关系，并鉴定了几种在体外对结核分枝杆菌具有低微摩尔活性的酰胺基和脲基类似物。大鼠体内的药代动力学为获得生物利用性化合物提供了一条途径。该系列具有良好的微生物学特征，在体外具有针对复制和非复制结核分枝杆菌的杀菌活性。。类似物对其他革兰氏阳性细菌的活性有限，但对革兰氏阴性细菌没有活性。我们的研究确定了该系列中的关键责任为细胞毒性。专注于鉴定靶标的未来工作可能有助于去除针对真核细胞的活性。

更新日期：2017-09-18

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