8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure–activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.

以马可嗪酮为代表的 8-硝基苯并噻嗪酮 (BTZ) 是一类新型抗结核药物，具有异常有效的活性。芳基硝基被认为对于活性是必不可少的，因为它在分枝杆菌内被黄素酶 DprE1 生物激活为共价标记 Cys387 的反应性亚硝基代谢物。然而，芳基硝基在安全性、稳定性和耐受性方面是一个潜在的缺点。在本文中，我们引入了腈作为硝基的生物电子等排替代品，我们假设它可以保持类似的共价抑制机制，但减轻上述担忧。 8-氰基苯并噻嗪酮1d显示出有效的抗结核活性，MIC 为 130 nM，并且在小鼠中具有改善的分布体积，与马可嗪酮相比，其内在半衰期延长了一倍。对1d的 C-2 取代基的分析揭示了与马可嗪酮相似的结构-活性关系。总体而言，结果证实苯并噻嗪酮的 8-硝基可以成功地被腈取代，以保留有用的活性和有利的药代动力学特性。