Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere

The synthesis and biological profile in vitro of a series of coumarin inhibitors of gyrase B bearing a N-propargyloxycarbamate at C-3′ of noviose is presented. Replacement of the 5-methylpyrrole-2-carboxylate of coumarin drugs with an N-propargyloxycarbamate bioisostere leads to analogues with improved antibacterial activity. Analysis of crystal structures of coumarin antibiotics with the 24 kDa N-terminal domain of the gyrase B protein provides a rational for the excellent inhibitory potency of C-3′ N-alkoxycarbamates.