Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity
2023
Dongguang Fan | Bin Wang | Giovanni Stelitano | Karin Savková | Olga Riabova | Rui Shi | Xiaomei Wu | Laurent R. Chiarelli | Katarína Mikušová | Vadim Makarov | Yu Lu | Yuzhi Hong | Chunhua Qiao
Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills <i>Mycobacterium tuberculosis</i> (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 <b>37</b> displays improved solubility and bioavailability compared to the lead compound. Additionally, compound <b>37</b> shows Mtb-killing ability in an acute infection mouse model.
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