The 1,8 naphthyridines, 4-quinolones, cinnolines. fluoroquinolones, and fluorinated naphthyridones, together with their important sidechain substituent modifications and resultant structure-activity relationships are summarized in Table I. Modifications to the nucleus converting the naphthyridine nitrogen in the 8-position to a carbon reduced adverse reactions and increased activity against Gram-positive cocci, including both streptococci and Staphylococcus aureus, whereas either piperazine or other ^-cyclic substitutions at the 7-position significantly increased potency against Gram-negative bacteria, including P
TABLE I A Chemical and Functional Classification of Quinolones and Fluoroquinolones
Structure Name Antibacterial activity Pharmacokinetics Indications/comments
First-generation compounds (often all included as 4-quinolones)
1,8 naphthyridine Nalidixic acid
(carboxylic acid) Piromidic acid 7-methyl 7-pyrrole
1,2-cinnoline Cinoxacin (carboxylic acid)
4-quinoIone (carboxylic acid) Oxolinic acid
7-piperazine (pyrido-pyrimidine) Pipemidic acid P. aeruginosa added
6,7,8 sidechain substituents Name N-l sidechain Antibacterial activity Pharmacokinetics Indications/comments
Enterobacteria only, no Orally absorbed, poor UTI, shigellosis significant anti-Gram- to moderate tissue positive activity penetration
Second-generation compounds (IIA)
A. Fluoroquinolones with enhanced but predominantly Gram-negative activity
Ciprofloxacin Cyclopropyl Pefloxacin Norfloxacin Ofloxacin (Levofloxacin: Rufloxacin
Gram-negative: less active than piperazinyl derivatives
Limited to UTI
Enhanced anti-Gram nega- High absorption, ++ tissue UTI, STD, enteric infec-
1-8 (S) cyclic ring tive potency, including P. aeruginosa plus some limited anti-Gram-positive activity penetration, variable elimination (renal/ metabolic) with moderate to long T/2
tions, RTI (not 1° pneumococcal), invasive Gram-negative infections: osteomyelitis, skin and soft tissue, etc.
6,8-difluoro-7-piperazinyl Lomefloxacin Ethyl
Second-generation compounds (IIB)
B. Fluoroquinolones with balanced broad spectrum activity
6-fluoro-7-piperaziny) 6,8-difluoro-7-dimethylpiperazinyl 6-fluoro-8-chloro-7-pyrrolodinyl 6-fluoro-7-pyrrolidinyl naphthyridone
Fluoroquinolones with enhanced Gram-positive activity
6-fluoro-7-azabicyclo naphthyridone Trovafloxacin Difluorophenyl
6-fluoro-8-methoxy-7-azabicyclo 6-fluoro-8-methoxy-7-piperazinyl and
Lesser anti-Grampositive activity
Long T/2: once daily
Lomefloxacin CNS toxic significantly phototoxic
Enhanced anti-Gram-positive potency, broad-spectrum and anti-pneumococcal activity
Long T/2: once daily high bioavailability, excellent respiratory penetration, few interactions (except grepa-floxacin)
1. All now superseded by more active third-generation agents.
2. Sgnificantly toxic -most withdrawn from clinical use.
Extended activity with ++ anti-pneumococcal and potential anti-anaerobic potency
As for second-generation agents
1. Highly active respiratory quinolones CAP/AECB.
2. Potential for surgical and Ob/Gyn infections.
aeruginosa. These 7-piperazine-substituted compounds, notably pipemidic acid (a pyrido-pyrimidine), were also active against some nalidixic acid-resistant enterobacteria. Subsequent fluorination at the 6-position further improved potency and added clinically exploitable Gram-positive potency . Even more potent compounds were produced by halogenation of the 8-position, notably the 8-chloro derivatives. Unfortunately, these proved highly phototoxic and have mostly been abandoned. Replacement with an 8-methoxy group has yielded the fluoroquinolones moxifloxacin and gatifloxacin, with markedly reduced photo-toxic potential but similarly enhanced potency. Specific molecular configurations, now including several des-fluorinated quinolones (one with an 8-difluoromethoxy substituent), and SARs are discussed in detail in Chapter 2. It is tempting to speculate, however, on the primacy of the 1-cyclopropyl (or 1-8 cyclic) substituent in determining safety from idiosyncratic quinolone toxicity. The only compounds—that is, temafloxacin, tosufloxacin, and trovafloxacin—to depart from this configuration all had 1(2,4)-difluorophenyl substitutions and all proved to have specific, commonly immunologically mediated, severe toxicities. It seems unlikely that new molecules with either this or indeed the 8-chloro configuration will be developed.
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