Discovery, Structure-Activity Relationships and Unique Properties of Non- Fluorinated Quinolones (NFQs)

ISSN: 2211-3533 (Online)
ISSN: 2211-3525 (Print)

Volume 15, 2 Issues, 2017

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Anti-Infective Agents

Formerly: Anti-Infective Agents in Medicinal Chemistry

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Discovery, Structure-Activity Relationships and Unique Properties of Non- Fluorinated Quinolones (NFQs)

Anti-Infective Agents, 2(1): 13-25.

Author(s): Benoit Ledoussal, Ji-In K. Almstead, Jeffrey L. Gray, Eric X. Hu and Siddhartha Roychoudhury.

Affiliation: Procter&Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-MontgomeryRoad, Mason, OH 45040, USA


The use of antibacterial antibiotics in therapy represents a huge selection pressure for bacteria leading to increasing levels of resistance to these agents. A more controlled usage of these drugs may be a way to partially counterbalance this bacterial evolution. However, the design of new agents active against resistant organisms remains of critical importance. 6-Fluorinated quinolones, like Ciprofloxacin, represent a very significant improvement over the first generation quinolones (e.g. nalidixic acid) in terms of potency, spectrum and pharmacodynamic properties. Unfortunately, once introduced in clinic, these agents faced a rapid emergence of resistance from gram-positive organisms. The subsequent efforts to improve the fluoroquinolones gram-positive spectrum were significantly hindered by the parallel existing between the fluoroquinolones gram-positive potency and their genotoxicity. Challenging the 6-fluorine dogma, it was found that by selecting the proper set of substituents at 1, 8 and 7 positions, broad-spectrum quinolones of very high gram-positive potency could be obtained. The potential of this non-fluorinated series became clearer when two independent reports showed that non-fluorinated quinolones were consistently less genotoxic than their 6-fluorinated counterparts. Additionally, the unique structure-activity relationships of 6-hydroquinolones and the finding of previously unreported resistance mutations induced by these agents are indications that these analogs may not interact with their target, the type II bacterial topoisomerases, in a way similar to typical fluoroquinolones. This set of unique properties makes the 6-hydroquinolones or Non-fluorinated Quinolones (NFQs) a very appealing platform from which new broad-spectrum agents with better potency against gram-positive pathogens can be identified.


non-fluorinated quinolones, nfqs, ciprofloxacin, nalidixic acid, fluoroquinolones.

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Article Details

Volume: 2
Issue Number: 1
First Page: 13
Last Page: 25
Page Count: 13
DOI: 10.2174/1568012033354531

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