Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis

• DOI: 10.1128/spectrum.04721-22
• Publication Date: 2023-09-12T13:00:57Z
• Authors: Wang Xiang; Hualong He; Xianjie Duan; Zhiqun He; Xinyue Xu; Mengya Liao; Fei Teng; Xiao Li; Tianwen Luo; Jumei Zeng; Luoting Yu; Chao Gao
• Keywords: Antimycobacterial; Bedaquiline

About a quarter of the world's population is infected with Mycobacterium tuberculosis, equivalent to about two billion people. With emergence multidrug-resistant those existing anti-tuberculosis drugs no longer meet demand for cure anymore; there an urgent need development new drugs. Decaprenylphosphoryl-β-D-ribose 2´-epimerase (DprE1) has been proven be potential antimycobacterial target, and several inhibitors have entered clinical trial. Herein, we designed synthesized series compounds based on indole benzomorpholine by using strategy scaffold hopping. The preferred compound B18 showed strong activity in H37Rv drug-resistant isolates. In addition, did not exhibit efficacy against other species strains. Subsequently, target was identified as DprE1 analyzing spontaneous compound-resistant mutation data, docking study performed illustrate binding mode between DprE1. general, compatible current inhibitors, even higher phosphodiesterase 6C selectivity plasma protein rate, which represent type effective reversible inhibitor. IMPORTANCE Drug therapy remains cornerstone tuberculosis (TB) treatment, yet first-line are associated significant adverse effects that can compromise patient outcomes. Moreover, prolonged widespread use led alarming rise strains including [MDR-tuberculosis (TB)] extensively (XDR-TB) forms. Urgent action needed develop novel agents capable overcoming these challenges. We report B18, decaprenylphosphoryl-β-D-ribose inhibitor backbone, exhibits potent only non-pathogenic strain H37Ra, but also pathogenic MDR XDR Preliminary druggability studies indicate possesses high safety acceptable pharmacokinetic properties, rendering it promising candidate further agent.