Trisubstituted imidazoles as Mycobacterium tuberculosis glutamine synthetase inhibitors.
Gising J, Nilsson MT, Odell LR, Yahiaoui S, Lindh M, Iyer H, Sinha AM, Srinivasa BR, Larhed M, Mowbray SL, Karlén A.
Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.