Richter Adrian, Seidel Rüdiger W, Goddard Richard, Eckhardt Tamira, Lehmann Christoph, Dörner Julia, Siersleben Fabienne, Sondermann Theresia, Mann Lea, Patzer Michael, Jäger Christian, Reiling Norbert, Imming Peter
Martin-Luther-Universität Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, 06120 Halle (Saale), Germany.
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany.
ACS Med Chem Lett. 2022 Jul 25;13(8):1302-1310. doi: 10.1021/acsmedchemlett.2c00215. eCollection 2022 Aug 11.
8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent antitubercular agents. BTZ043 as one of the most advanced compounds has reached clinical trials. The putative oxidation products of BTZ043, namely, the corresponding BTZ sulfoxide and sulfone, were reported in this journal (Tiwari et al. , , 128-133). The molecular structures were later revised to the constitutionally isomeric benzisothiazolone and its 1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones (BITs) with in vitro activity against mycobacteria. The constitutionally isomeric -acyl benzisothiazol-3-ols, in contrast, show little or no antimycobacterial activity in vitro. The structures of the four compounds were investigated by X-ray crystallography and NMR spectroscopy. Molecular covalent docking of the new compounds to decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) suggests that the active BITs exert antimycobacterial activity through inhibition of DprE1 like BTZs.
8-硝基-1,3-苯并噻嗪-4-酮（BTZs）是一类已知的强效抗结核药物。BTZ043作为其中最先进的化合物之一已进入临床试验阶段。BTZ043的推定氧化产物，即相应的BTZ亚砜和砜，已在本期刊中报道（蒂瓦里等人，，128 - 133）。其分子结构后来分别修订为结构异构体苯并异噻唑酮及其1-氧化物。在此，我们报道了两种具有抗分枝杆菌体外活性的源自BTZ043的苯并异噻唑啉酮（BITs）。相比之下，结构异构体α-酰基苯并异噻唑-3-醇在体外几乎没有或没有抗分枝杆菌活性。通过X射线晶体学和核磁共振光谱对这四种化合物的结构进行了研究。新化合物与癸异戊二烯基磷酸化-β-D-核糖2'-表异构酶（DprE1）的分子共价对接表明，活性BITs通过像BTZs一样抑制DprE1发挥抗分枝杆菌活性。
