Hybridization of Fluoroquinolones in the Search for New Antimicrobials

Introduction

Antibiotic resistance has grown continuously since these drugs were first used clinically. Today, the creation of new antimicrobials remains a constant race against the ability of pathogens to adapt and infect humans. However, instead of designing entirely new molecules, existing antibiotics can be chemically modified to increase their potency and bypass bacterial defenses. Fluoroquinolones (FQs) are ideal candidates for this approach, as their well-established antibacterial core is highly adaptable to structural modifications.

Methods

At first, docking studies were conducted based on such initial starting molecules as ciprofloxacin and norfloxacin. Then, methods of organic synthesis were used to synthesize the most promising molecules and develop suitable synthetic procedures. The structures and purity of the obtained compounds were determined using ¹H NMR, ¹³C NMR, LC/MS spectroscopy and X-Ray diffraction studies.

Results

Docking simulations against PDB targets 2XCR and 4KPF identified potent candidates targeting Gram-positive and Gram-negative pathogens. The resulting data established key pharmacophore requirements, including a fluorine atom at C-6, a heterocyclic moiety at C-7, and a phenylsulfonyl residue attached to the C-3 position. Guided by these structure-activity relationships, we synthesized a few novel series of hybridized FQs. The target compounds were isolated in moderate yields.

Conclusions

Incorporating a 1,2,3-triazole moiety into the starting structures led to novel derivatives with moderate antimicrobial activity. However, introducing C-3 arylsulfonyl substituents compromised the compounds' solubility profiles, leading to a slight decrease in efficacy compared to the triazole analogues.