Discovery of novel pyrimidinetrione derivatives as DprE1 inhibitors with potent antimycobacterial activities

Abstract

Tuberculosis (TB) is one of the ten major factors threatening human life and health. At present, many factors limit the application of existing anti-tuberculosis drugs, such as a small range of available drug options, poor treatment compliance, and severe toxic and side effects. It is extremely urgent to develop novel anti-tuberculosis drugs. DprE1 is a potential anti-mycobacterial cell wall target, and some DprE1 inhibitors have entered the clinical research stage. Our research group found DprE1 inhibitor G50 with similar activity as isoniazid through virtual screening in the early stage. To obtain better DprE1 inhibitors, 45 new compounds were designed and synthesized based on the structure of G50. Among them, 12 selected DprE1 enzyme inhibitors could significantly inhibit the growth of Mycobacterium tuberculosis (M.tb) H37Ra and H37Rv growth in vitro. The MIC₅₀ value of compound 42 against M.tb H37Ra is 1.071 ± 0.041 μM, with the selective index (SI) value of 186.74 (the SI value of linezolid is 119.9). Compared to G50, compound 42 exhibits a 5-fold increase in DprE1 enzyme inhibitory activity. In addition, the binding affinity of compound 42 is equivalent to that of G50. This study further enriches the examples of developing DprE1 inhibitors based on the backbone of pyrimidinetrione and also provides potential anti-tuberculosis lead compounds.