Structure Activity Relationships SARs

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

Improved absorption

Limited to UTI

Enhanced anti-Gram nega- High absorption, ++ tissue UTI, STD, enteric infec-

Ethyl Ethyl


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

Fleroxacin Fluoro-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













Third-generation compounds

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


Moxifloxacin Gatifloxacin

Cyclopropyl Cyclopropyl

Gemifloxacin Cyclopropyl

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.

3. Possible pediatric use.

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 [3]. 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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