Antibiotic resistance presents a growing problem for the treatment series infections.  We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors.  Starting from a virtual screening hit, potency was optimized through a combination of structure-based design and incorporation of substituents established in other series.  Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56 �M.  These compounds inhibit both topoisomerase subtypes II and IV at similar nanmolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based resistance.

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV

243rd National Meeting (2012)

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