Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: Novel antibacterial agents against Mycobacterium tuberculosis

Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6 μg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents.

Graphical abstractSeveral 1,4-benzoxazines were identified in a HTS directed at MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase in the Mycobacterium tuberculosis menaquinone biosynthesis pathway. Subsequent SAR studies resulted in the discovery of compounds with MIC values as low as 0.6 μg/ml against H37Rv.Figure optionsDownload full-size imageDownload as PowerPoint slide