Synthesis and evaluation of thiazolyl-1H-benzo[d]imidazole inhibitors of Mycobacterium tuberculosis inosine monophosphate dehydrogenase

Abstract

Using an orthologue-based design approach, we synthesized and assayed a series of thiazolyl-1H-benzo[d]imidazole derivatives as inhibitors of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase (MtIMPDH). From these experiments, a benzo[d] imidazole compound was described to inhibit the enzyme in the low micromolar range (KiIMP = 0.55 ± 0.02 μM), which places this compound among the most potent in vitro MtIMPDH inhibitors developed to date. In addition, steady-state kinetic measurements and docking simulations were employed to determine its inhibition and interaction modes. The results described herein may be useful for the design and development of novel alternative therapeutics for tuberculosis that target MtIMPDH, a predicted to be essential (for optimal in vitro bacillus growth), druggable and assayable molecular target.