Fan Dongguang, Wang Bin, Stelitano Giovanni, Savková Karin, Riabova Olga, Shi Rui, Wu Xiaomei, Chiarelli Laurent R, Mikušová Katarína, Makarov Vadim, Lu Yu, Hong Yuzhi, Qiao Chunhua
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research, Beijing Chest Hospital, Beijing 101149, China.
Biomedicines. 2023 Jul 12;11(7):1975. doi: 10.3390/biomedicines11071975.
Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound displays improved solubility and bioavailability compared to the lead compound. Additionally, compound shows Mtb-killing ability in an acute infection mouse model.
结核病（TB）是一种具有严重抗生素耐药性的主要传染病。苯并噻嗪酮（BTZ）骨架的PBTZ169通过抑制必需的细胞壁酶癸酰磷酸基-β-D-核糖2'-氧化酶（DprE1）来杀死结核分枝杆菌（Mtb）。PBTZ169在动物模型和初步临床试验中显示出抗结核潜力。尽管效力很强，但一般来说，BTZ型DprE1抑制剂的水溶性极低，这对药物样性质产生不利影响。为了改善化合物的物理化学性质，我们合成了一系列BTZ类似物。几种优化后的化合物对Mtb的最低抑菌浓度（MIC）值低于0.01µM。与先导化合物相比，代表性化合物的溶解度和生物利用度有所提高。此外，化合物在急性感染小鼠模型中显示出杀死Mtb的能力。
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