Due to growing bacterial resistance towards conventional antibiotics, it is critical that novel antimicrobial targets are explored.  Histidine kinases (HKs), integral elements of two-component systems (TCS), are promising targets as they are ubiquitous among bacteria and contain a number of conserved structural motifs. TCS serve crucial functions in bacteria, having been implicated in regulating growth, motility, and virulence. To widely inhibit multiple HKs, we believe targeting the highly conserved ATP binding domain is one strategy for developing a broad-spectrum antibiotic. We have found that biaryl-pyrazoles moderately inhibit HKs, but our synthetic route to biaryl-pyrazole scaffolds has proven inefficient, delaying exploration of novel motifs. We hypothesize that a biaryl-triazole scaffold, which can be readily accessed via click chemistry cycloaddition, is a suitable replacement for the biaryl-pyrazole scaffold due to similar spatial and electronic properties. To access this structure, we use the ruthenium catalyzed 1,3-cycloaddition approach. Efficient and highly yielding, this approach provides rapid access to a diverse set of molecules, facilitating the exploration of structure-activity relationships between these inhibitors and HKs. We report the synthesis of a small panel of biaryl-triazole compounds and their <i>in vitro </i>activity against CckA, an essential HK found in <i>Caulobacter crescentus</i>.

Click chemistry cycloaddition approach to inhibitors of histidine kinases

251st National Meeting (2016)

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