Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents

Our
strategy to combat resistant bacteria consisted of targeting the GyrB/ParE
ATP-binding sites located on bacterial DNA gyrase and topoisomerase
IV and not utilized by marketed antibiotics. Screening around the
minimal ethyl urea binding motif led to the identification of isoquinoline
ethyl urea 13 as a promising starting point for fragment
evolution. The optimization was guided by structure-based design and
focused on antibacterial activity in vitro and in vivo, culminating
in the discovery of unprecedented substituents able to interact with
conserved residues within the ATP-binding site. A detailed characterization
of the lead compound highlighted the potential for treatment of the
problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch
therapy was supported by the identification of a suitable prodrug
concept. Eventually, hERG K-channel block was identified as the main
limitation of this chemical series, and efforts toward its minimization
are reported.