Structural Characterization of the Millennial Antibacterial (Fluoro)Quinolones—Shaping the Fifth Generation

Abstract

The evolution of the class of antibacterial quinolones includes the introduction in therapy of highly successful compounds. Although many representatives were withdrawn due to severe adverse reactions, a few representatives have proven their therapeutical value over time. The classification of antibacterial quinolones into generations is a valuable tool for physicians, pharmacists, and researchers. In addition, the transition from one generation to another has brought new representatives with improved properties. In the last two decades, several representatives of antibacterial quinolones received approval for therapy. This review sets out to chronologically outline the group of approved antibacterial quinolones since 2000. Special attention is given to eight representatives: besifloxacin, delafoxacin, finafloxacin, lascufloxacin, nadifloxacin and levonadifloxacin, nemonoxacin, and zabofloxacin. These compounds have been characterized regarding physicochemical properties, formulations, antibacterial activity spectrum and advantageous structural characteristics related to antibacterial efficiency. At present these new compounds (with the exception of nadifloxacin) are reported differently, most often in the fourth generation and less frequently in a new generation (the fifth). Although these new compounds’ mechanism does not contain essential new elements, the question of shaping a new generation (the fifth) arises, based on higher potency and broad spectrum of activity, including resistant bacterial strains. The functional groups that ensured the biological activity, good pharmacokinetic properties and a safety profile were highlighted. In addition, these new representatives have a low risk of determining bacterial resistance. Several positive aspects are added to the fourth fluoroquinolones generation, characteristics that can be the basis of the fifth generation. Antibacterial quinolones class continues to acquire new compounds with antibacterial potential, among other effects. Numerous derivatives, hybrids or conjugates are currently in various stages of research.

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

“…Currently, FQs whose predominant species at physiological pH is not a zwitterion are under development and exist in clinical use. Delafloxacin, a fourth generation FQ registered for use in humans, is an anionic non-zwitterionic molecule, with poor presence of cationic microspecies, only at extreme acidic pH and uncharged at acid pH [ 42 , 43 , 44 ]. As the balance of the species is pH-dependent, the solubility of FQs also varies depending on the medium and the solvent in which it is found.…”

“…The combination of fluorine at C6, the piperazinyl ring at C7, and cyclopropyl at N1 increased the potency of ciprofloxacin to inhibit the activity of E.coli gyrase nearly 200-times, relative to nalidixic acid [ 66 , 72 ]. Importantly, the introduction of fluoride explains the improvement in the pharmacokinetic profile of FQs and became the dogmatic characteristic of the group, however, today there are new non-fluorinated molecules such as nemonoxacin [ 5 , 44 , 73 ].…”

“…Molecules with methoxy group substituents at C8 or halogens have been reported to have higher activity against resistant strains of S. aureus and Mycobacterium smegmatis compared to ciprofloxacin [ 76 ]. Today, approved molecules with a Cl − at position C8, such as besifloxacin, which also replaces the piperazinil group with a 3-aminohexahydro-1H-azepine, expand the global activity against Gram-positive [ 44 ]. Therefore, C8-halogenated derivatives with a fluorine, such as lomefloxacin, have been associated with a higher incidence of photosensitivity [ 5 , 66 ].…”

“…Various FQs have been withdrawn from the market due to severe safety concerns, including those with an N1-difluorobenzene such as temafloxacin and trovafloxacin that caused severe hemolysis and hepatotoxicity, respectively [ 5 ]. Sparfloxacin and grepafloxacin, from the family of C5 substituents, were also removed for cardiotoxicity [ 5 , 44 ].…”

“…Since their discovery, thousands of molecules have been synthesized and despite the safety problems presented by some fluoroquinolones, the study of new substituents and the introduction of new fluoroquinolones in the pharmaceutical market has continued [ 44 , 77 ]. Examples of the above are the FDA approvals of the FQs besifloxacin, delafloxacin, and finafloxacin.…”