Fluoroquinolones 341 History

The fluoroquinolones are a synthetic class of antibacterial drugs discovered by the Sterling-Winthrop Institute in 1962 as an impurity during synthesis of the antimalarial compound chloroquine [225]. This byproduct, nalidixic acid (Fig. 18; 16a), was approved by the FDA in 1963 to treat Gram-negative urinary tract infections.

JL J

Norfloxacin 16b

Ciprofloxacin 16c

Naldixic Acid 16a

^VCX

0floxacin 16d

Levfloxacin 16e

Fig. 18 First- and second-generation fluoroquinolones

co2h

However, despite its good bioavailability and straightforward synthesis, nalidixic acid has had limited clinical use due to a poor pharmacokinetic profile and narrow antibacterial spectrum [226]. Interest in the quinolones was renewed in 1980 with the discovery of the first reported antibacterial fluoroquinolone, norfloxacin (Fig. 18; 16b), by the Dainippon Pharmaceutical Company [227]. Norfloxacin showed broad spectrum antibacterial activity 1,000-fold greater than nalidixic acid [228, 229] as well as improved pharmacokinetic properties, with a longer half-life and improved solubility [228-230]. Norfloxacin and several other second-generation fluoroquinolones such as ciprofloxacin (Fig. 18; 16c) (first reported in 1982 by Bayer [231]), ofloxacin (Fig. 18; 16d) (first reported in 1983 by Daiichi Pharmaceutical Co., Ltd., now Daiichi Sankyo Co., Ltd. [232]), and levofloxacin (Fig. 18; 16e), which is the isolated S-isomer of racemic mixture ofloxacin (also developed by Daiichi Pharmaceutical Co., Ltd. [232]), have proven relatively safe and remain among the most frequently prescribed drugs [226].

Following the discovery of norfloxacin (16b), SARs for the fluoroquinolone core were studied in detail. This led to the development of a number of analogs with broader antibacterial activity, better solubility, and longer serum half-lives [226, 229]. Among the third and fourth generations of fluoroquinolones, moxifloxacin (Fig. 18; 16f) (developed in 1991 by Bayer [233]), which has a bulky hydrophobic modification at C(7), has been the most successful. Unfortunately, several third and fourth generation agents have been restricted or withdrawn due to severe adverse effects (Fig. 19) including temafloxacin (16g), grepafloxacin (16h), trovafloxacin (16i), and clinafloxacin (16j) [226, 234, 235].

Many new fluoroquinolones are in development such as gemifloxacin (Fig. 20; 16n), patented in 1998 by LG Life Sciences Ltd. [236], and sitafloxacin (Fig. 20; 16o) (first reported in 1994 by Daiichi Seiyaku Co. [237]) which show activity against a panel of respiratory pathogens [229]. Sitafloxacin is currently in clinical development;

Moxifloxacin 16f

(black box warning)

Moxifloxacin 16f

(black box warning)

Temafloxacin

16g (withdrawn)

CH3 O

Grepafloxacin 16h (withdrawn)

Trovafloxacin 16i

(withdrawn)

Clinafloxacin 16j

(withdrawn)

Gatifloxacin 16k

(oral and injectable not available in US)

Grepafloxacin 16h (withdrawn)

Lomefloxacin 16l

(black box warning)

Lomefloxacin 16l

(black box warning)

NH2 O

Sparfloxacin

16m (no longer available in US)

Fig. 19 Third- and fourth-generation fluoroquinolones

Fig. 20 New DNA gyrase inhibitors h2n yj ^

h3co-n

Gemifloxacin 16n

(black box warning)

1 1 h2n

Sitafloxacin 16o

^co2h och3

och3

Gemifloxacin 16n

(black box warning)

och3

och3

GSK299423 16p

GSK299423 16p

co2h

Viquidacin (NXL101) 16q

(development discontinued)

Fig. 21 Fluoroquinolone SAR (adapted from [229, 242, 243])

Affects potency;

small polar groups preferred;

affects activity spectrum

Required for_

potency

Binds DNA gyrase; required for transport into bacteria

Affects potency and PK; _ determines activity spectrum

Affects activity spectrum and PK; small, electron-deficient preferred

Binds DNA gyrase; required for transport into bacteria

Sterically undemanding groups required

\ Electron-deficient and sterically strained preferred gemifloxacin is a clinically prescribed drug. Recently, novel bacterial topoisomerase inhibitors (NBTIs) with modes of action similar to the fluoroquinolones have been reported, including GSK 299423 (Fig. 20; 16p) [238], NXL101 (Fig. 20; 16q) [239], and a series of tetrahydroindazole compounds [240, 241]. While these new compounds have shown good in vitro activity against a spectrum of both Gram-positive and Gram-negative microbes including strains resistant to fluoroquinolones, it remains to be seen whether they will also exhibit activity toward MTb.

3.4.2 Structure-Activity Relationships

While the SAR of the fluoroquinolones has not been analyzed specifically for mycobacteria, it is reasonable to assume that many of the relationships found in other types of bacteria will be applicable to MTb (Fig. 21). Modifications at N(1) control potency, with electron-poor and sterically strained cyclopropyl being optimal, followed by 2,4-difluorophenyl and t-butyl [242]. This substituent also controls Gram-negative and Gram-positive activities, and a 2,4-difluorophenyl group increases activity against anaerobes. The C(2) position is near the DNA gyrase-binding site, and thus a sterically undemanding hydrogen atom at R2 is optimal [244]. The dicarbonyl moiety is required for binding to DNA gyrase and thus is critical for activity. Modifications at C(5) control in vitro potency with the most active groups being small electron-rich groups such as -NH2, -OH, and -CH3 [242]. Additionally, C(5) modifications affect activity against both Gram-negative and Gram-positive organisms. The fluorine atom at C(6) (for which the class is named) enhances DNA gyrase inhibition [226, 244] and can increase the MIC of the compound 100-fold over that of other substitutions [242]. The most active substituents at C(7) have been five- and six-membered nitrogen heterocycles, with pyrrolidines increasing activity against Gram-negative bacteria and piperazines affecting potency against Gram-positive organisms. The C(8) position controls absorption and half-life, and optimal modifications for in vivo efficacy include groups that create an electron-deficient pi system, i.e., N, CF, and CCl [245]. Several modifications that create a N(1) to C(8) bridge have also been successful, i.e., ofloxacin (Fig. 18; 16d) and levofloxacin (Fig. 18; 16e), which both display significant gyrase inhibition [244].

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