Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis glutamine synthetase inhibitors
2012; Royal Society of Chemistry; Volume: 3; Issue: 5 Linguagem: Inglês
10.1039/c2md00310d
ISSN2040-2511
AutoresAnneli Nordqvist, Mikael Nilsson, Olof Lagerlund, Daniel Muthas, Johan Gising, Samir Yahiaoui, Luke R. Odell, B. R. Srinivasa, Mats Larhed, Sherry L. Mowbray, Anders Karlén,
Tópico(s)Tuberculosis Research and Epidemiology
ResumoBased on an imidazo[1,2-a]pyridine hit from a high-throughput screening directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a number of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 μM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified with single-digit micromolar potency and one with sub-micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize many of the structure–activity relationships observed.
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