Design, synthesis and characterization of dual inhibitors against new targets FabG4 and HtdX of Mycobacterium tuberculosis

• Mycobacterium FabG4 and HtdX are selected as new anti-TB targets.
• Dual inhibitors are designed through structure-based and ligand-based approaches.
• Accomplishment of synthesis of designed compounds is reported.
• Inhibition kinetics, ITC, CD measurements demonstrated the target enzyme inhibition.
• MIC and biofilm inhibition assays highlighted the potential as new class of anti-TB agents.

Herein, we present dual inhibitors of new targets FabG4 and HtdX for the first time. In this work, eight compounds have been designed, synthesized, characterized and evaluated for bio-activities. Amongst them, six compounds have shown inhibitory activities. Three of them (12–14) demonstrate dual inhibition of both FabG4 and HtdX at low micromolar concentration. In addition, the dual inhibitors show good anti-mycobacterial properties against both planktonic growth and biofilm culture of Mycobacterium species. This study is an important addition to tuberculosis drug discovery because it explores two new enzymes as drug targets and presents their dual inhibitors as good candidates for pre-clinical trials.

Dual inhibitors 5a-5c of new targets FabG4 and HtdX of Mycobacterium tuberculosis are reported.Figure optionsDownload as PowerPoint slide