2H-Benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes. Specifically, three β-CAs (MtCA1, MtCA2, and MtCA3) were identified in Mycobacterium tuberculosis and their inhibition was shown to exert an antitubercular action. BTDs derivatives 2a-q effectively inhibited the mycobacterial CAs, especially MtCA2 and MtCA3, with Ki values up to a low nanomolar range (MtCA3, Ki = 15.1–2250 nM; MtCA2, Ki = 38.1–4480 nM) and with a significant selectivity ratio over the off-target human CAs I and II. A computational study was conducted to elucidate the compound structure-activity relationship. Importantly, the most potent MtCA inhibitors demonstrated efficacy in inhibiting the growth of M. tuberculosis strains resistant to both rifampicin and isoniazid—standard reference drugs for Tuberculosis treatment.

中文翻译：

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苯并噻二嗪酮-1,1-二氧化碳酸酐酶抑制剂抑制耐药结核分枝杆菌菌株的生长

本文探索基于 2H-苯并[e][1,2,4]噻二嗪-3(4H)-酮 1,1-二氧化物 (BTD) 的碳酸酐酶 (CA) 抑制剂作为新型抗分枝杆菌药物。BTD衍生物的化学特征符合有效抑制β-类CA同工酶的标准。BTD 衍生物的化学特征符合有效抑制 β 类 CA 同工酶的标准。具体而言，在结核分枝杆菌中鉴定出三种 β-CA（MtCA1、MtCA2 和 MtCA3），并且对它们的抑制显示出抗结核作用。BTD 衍生物 2a-q 有效抑制分枝杆菌 CA，尤其是 MtCA2 和 MtCA3，Ki 值高达低纳摩尔范围（MtCA3，Ki = 15.1–2250 nM；MtCA2，Ki = 38.1–4480 nM），并且具有显着的选择性比超过脱靶人类 CA I 和 II。进行了计算研究以阐明化合物的结构-活性关系。重要的是，最有效的 MtCA 抑制剂能够有效抑制对利福平和异烟肼（结核病治疗的标准参考药物）耐药的结核分枝杆菌菌株的生长。