Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.

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The Cover Feature shows the conceptual conversion of clinafloxacin to its tetracyclic analog by addition of a 7‐membered ring, thereby conformationally fixing the amino‐pyrrolidine ring out of plane from the bicyclic quinolone core. The compound is shown bound to one of its targets, topoisomerase IV from S. pneumoniae (PDB 4kpf, I. Laponogov et al., Open Biol. 2016, 6, DOI: 10.1098/rsob.160157) and stacking to its DNA template, depicted schematically in orange. The modification of this fluoroquinolone core resulted in a remarkable enhancement of microbiological potency toward both Gram‐positive and Gram‐negative bacteria. This presents an excellent advantage in our fight against multidrug‐resistant bacteria. More information can be found in the Communication by Heinz E. Moser et al. on page 1687 in Issue 20, 2017 (DOI: 10.1002/cmdc.201700426).