Identification of the mode of action and cellular targets of known bactericidal agents is crucial for developing new drugs against Mycobacterium tuberculosis (Mtb). We have synthesized and evaluated a series of 2-aminothiazoles (ATs) for structure-activity relationship (SAR) detemination and identified a number of analogs that possess excellent activity against Mtb with rapid kill kinetics. However, the mode of action of this series is unknown. Furthermore, analogs of this series demonstrated poor pharmacokinetic (PK) properties. Thus, identifying the biological target for this series is vital for the strucutre-based design of novel AT compounds with enhanced PK properties. To this end, we have designed and synthesized AT-based molecular probes to elucidate the biological targets and cellular processes linked to bactericidal activity and mode of action. The synthesis and biological evaluation of AT analogs, as well as initial target identification studies of AT-based probes will be presented.

Design, synthesis and target validation studies of aminothiazoles (ATs) as potent inhibitors of <i>Mycobacterium tuberculosis</i>

247th National Meeting (2014)

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Design, synthesis and target validation studies of aminothiazoles (ATs) as potent inhibitors of Mycobacterium tuberculosis