The substrate-binding pocket of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is large in comparison to homologous enoyl-ACP reductases (FabI) from different organisms. This presents a unique opportunity to probe the chemical space in this region and determine if residence time is correlated to size of the inhibitor side chain. A series of inhibitors based on the diphenyl ether scaffold have been synthesized using click chemistry and exhibit good minimum inhibitory concentrations (MICs). The compound with the most potent MIC has the longest residence time of all InhA inhibitors known to date. The residence time, or the lifetime of a drug-target complex has important implications on therapeutic efficacy but can also be exploited as an informative chemical tool in applications ranging from radioimaging to assay development.  Using the best 'click chem' analog as a starting point, efforts are underway to incorporate radiolabelled 18F into the structure for the purpose of imaging infection and for extracting important pharmacokinetic information. Residence time is also being exploited to address the question of target occupancy, which will provide direct information on a target's vulnerability.

Design and synthesis of long residence time inhibitors and its application in radioimaging and assay development

246th National Meeting (2013)

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