Redefining Fluoroquinolone Antibiotics: Design and Synthesis of Degradable Fluoroquinolones to Reduce Environmental Persistence

A significant challenge associated with antibiotics, and active pharmaceutical ingredients in general, is their intentional design for high stability, which promotes environmental persistence and contributes to the development of antibiotic resistance. Ciprofloxacin, a widely used fluoroquinolone antibiotic, exemplifies this issue. Using the benign by design (BbD) approach, ciprofloxacin was redesigned into an environmentally improved fluoroquinolone molecule, termed Cip-hemi. In this design, ciprofloxacin was modified by replacing the persistent cyclopropyl group at the N1 position with a tetrahydrofuran moiety, thereby creating a degradable linker. Herein, we report the development of an efficient and robust synthetic platform to access the Cip-hemi scaffold, along with the preparation of a series of novel derivatives. These molecules are developed with a dual-purpose design: to restore high-level antibacterial action while ensuring rapid degradation in the aquatic environment. The optimized synthetic strategy minimizes the use of hazardous solvents and largely avoids labor-intensive purification by flash chromatography, providing a streamlined approach for the preparation of environmentally improved fluoroquinolones.