Fluoroquinolones and Their Hybrid Derivatives: Evolution, Mechanism of Action, Structure–Activity Relationships, Resistance, Therapeutic Relevance, and Recent Advances in Hybrid Drug Design

Abstract

Fluoroquinolones (FQs) are synthetic broad-spectrum antibacterials, and due to their potent bactericidal activity and favorable pharmacokinetic properties they have been a major player in the modern chemotherapy of bacterial infections. The main antibacterial action of these compounds is the inhibition of bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, by stabilization of drug-enzyme-DNA cleavage complexes that cause lethal DNA damage . Since their origin from nalidixic acid and early quinolones, systematic medicinal chemistry optimization, particularly fluorine substitution at the C-6 position and heterocyclic modification at C-7, has produced multiple generations of clinically important agents including ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin. Newer members such as finafloxacin, besifloxacin, zabofloxacin and delafloxacin have attracted interest in recent decades because of enhanced potency in certain infection settings and potential advantages against resistant pathogens. However, the clinical utility of fluoroquinolones has been limited by rising resistance rates stemming from target-site mutations, efflux pump overexpression, decreased permeability and plasmid-mediated resistance mechanisms. Safety concerns such as tendinopathy, dysglycemia, QT prolongation, effects on the central nervous system and phototoxicity have led to further restrictions on the use of some agents. Nonetheless, the quinolone scaffold is a privileged pharmacophore with well-defined structure-activity relationships (SAR) and excellent synthetic versatility. Hybridising fluoroquinolones with other pharmacophores has become an attractive strategy to enhance antibacterial potency, overcome resistance, and expand the biological spectrum to include antimycobacterial, antiviral, antifungal, and anticancer applications. The review highlights historical development, mechanism, SAR trends, resistance mechanism, clinical and emerging FQs, and modern hybrid and fused heterocyclic fluoroquinolone derivatives with focus on recent literature advances.