Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones

Abstract

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.

Keywords: antibiotics; antimicrobial spectrum; fluoroquinolones; gyrase; structure-activity relationships; topoisomerase.