Which of the following are quinolones?

A Fluoroquinolone Antibiotics

Although quinolone antibiotics have been around since nalidixic acid, the addition of a fluorine group to the quinolone moiety revolutionized this family and created the fluoroquinolones (Dalhoff and Schmitz, 2003). There have been more than 10,000 fluoroquinolone agents synthesized and tested since the original discovery of nalidixic acid in 1962 (Mah, 2003). Currently, the fluoroquinolones (moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin) represent the leading antibiotic ophthalmic products. They block bacterial DNA synthesis by inhibiting one of the enzymes (DNA gyrase, topoisomerase) needed in this process. The fluoroquinolone family is still being researched and harvested. Fluoroquinolones are useful in the prevention and treatment of a variety of ocular infections; however, resistance to this class has been emerging (Alexandrakis et al., 2000; Blondeau, 2004). Newer family members have better coverage. Beginning in 2003, the topical ocular fourth-generation fluoroquinolones, moxifloxacin and gatifloxacin, were approved for treating bacterial conjunctivitis. These antibiotics represent the most advanced group of compounds within the class, offer a unique dual-binding mechanism of action in gram-positive organisms, and have activity against otherwise resistant species (Blondeau, 2004). They are more active than either earlier fluoroquinolones or tobramycin, based on minimum inhibitory concentrations (MICs) and susceptibility results. In vivo studies using prophylactic models with rabbits have shown the potency of these antibiotics in preventing infections by common pathogens (Aliprandis et al., 2005; Dajcs et al., 2001; Kowalski et al., 2004). Also, active ingredients that are innately antimicrobial, such as antibiotics like the fluoroquinolones, have the opportunity to be formulated in multiple-dose containers without added antimicrobial preservative agents, such as benzalkonium chloride. This preservative has served the ophthalmic community well over the last 50 years, and is still required for preserving IOP-lowering and other ophthalmic products, but researchers generally avoid additional or unnecessary chemicals in any ophthalmic formulation. All fluoroquinolone ophthalmic products available in Japan are benzalkonium chloride-free. These are the “products to beat” in the future.

7.06.10.1 Anti-Infective Agents

7.06.10.1.1 Antibacterial agents

Similar to quinolone antibiotics, the naphthyridone derivative gemifloxacin mesilate 83 is an antibacterial compound <1999EP688772>. Trovafloxacin 84, another naphthyridone derivative, is also an active antibacterial <1998EP0676199>. A quinolone compound containing a disubstituted piperidine ring, moxifloxacin hydrochloride 85, is an ophthalmic antibacterial agent <1992DEA4208789>.

7.06.10.1.2 Antibiotics

Telithromycin 86 is a macrolide containing a 3-substituted pyridine and is used as an antibiotic <1998EP0680967>.

7.06.10.1.3 Antiviral agents (HIV/AIDS)

Atazanavir 87, a 2-arylsubstituted pyridine derivative, is used as an antiviral AIDS drug <1998USP5849911>. Nelfinavir mesilate 88 has found use as an antiviral agent <1994DDR1043>. Potential drugs for HIV inhibition that contain pyridine functionalities are Sch-C 89 and Sch-D 90 <2003MI30>.

7.19.1.2 Brief History of Quinolone Agents

The family of quinolone antibiotics sprang from the discovery of nalidixic acid (1) by George Lesher and coworkers in 1962.5 The original lead compound, a 7-chloro-4-quinolone (10), was a by-product isolated from a recrystallization mother liquor during the synthesis of chloroquine. Thus, modern fluoroquinolones can trace their linage back to a serendipitous offshoot of antimalarial research. In the clinic, nalidixic acid (1), which is excreted in urine, was primarily used for the treatment of uncomplicated UTI caused by Gram-negative microbes such as Escherichia coli, Klebsiella, and Proteus spp. Unfortunately due to its poor activity against Gram-positive organisms, lack of potency against P. aeruginosa, inadequate serum concentrations, poor tissue distribution, and frequent incidence of adverse effects, nalidixic acid's utility and benefits were limited.6 However, the discovery of nalidixic acid inspired a rush of innovative research and development leading to a new class of antibiotic.

Introduced into the clinic in the 1970s, compounds such as oxolinic acid,7 cinoxacin8 and pipemidic acid gave marginal improvement over nalidixic acid (Figure 1). These agents still lacked broad-spectrum activity and had modest serum levels, but could be dosed twice daily to treat UTI. The discovery of the first fluoroquinolone, norfloxacin (11), led to a marked improvement in the activity against Gram-negative species, including P. aeruginosa. Norfloxacin was also active against problematic bacteria such as gentamicin-resistant P. aeruginosa, penicillin-resistant Neisseria gonorrhoeae, Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus. However, unlike with S. aureus, norfloxacin had less activity against most other aerobic, Gram-positive organisms and very little effect on anaerobic bacteria.9 While the enhanced Gram-negative activity due to the C-6 fluoro group was a breakthrough, norfloxacin, with high kidney concentrations and renal excretion as the major route of elimination, was still mostly limited to the treatment of UTI. However, the UTI cure rate using norfloxacin was improved over nalidixic acid, oxolinic acid, and cinoxacin.10 While high-sustained serum concentrations were difficult to attain, the drug concentrated in prostatic tissues and bile leading to some utility in treating bacterial prostatitis and gastroenteritis.11

A subtle change from the N-1 ethyl of norfloxacin to an N-1 cyclopropyl group led to the discovery of ciprofloxacin in the 1980s. To date, this fluoroquinolone maintains the most potent spectrum of activity against Gram-negative pathogens and an improved profile of activity against Gram-positive bacteria.12,13 Combining its extended spectrum activity and improved pharmacokinetic profile (e.g., improved Cmax, volume of distribution and bioavailability), ciprofloxacin became the first quinolone used for treating infections outside of UTI.14 The favorable pharmacokinetics and extended half-life allowed for twice-daily dosing while maintaining a minimal potential for adverse side effects.13 Because of its impressive Gram-negative spectrum, ciprofloxacin, typically in combination with a Gram-positive agent, continues to find wide application in the treatment of hospital-acquired and serious resistant infections, including RTI and UTI. However, due to relatively modest activity against strains of S. pneumoniae, ciprofloxacin has limited utility for treatment of common RTIs such as CAP.15

1.12.2.8 Synthetic Antimicrobials

Nalidixic acid, the first quinolone antibiotic, was approved in 1963. Later derivatives such as quinolones (and fluoroquinolones) block DNA replication and repair. They inhibit DNA gyrase and are active against Gram-positive and Gram-negative pathogens. The most well-known quinolones are ciprofloxacin, levofloxacin, and ciprofloxaxin. New antibiotics being examined in phase III clinical trials against TB include two fluoroquinones.

Another important new antibiotic introduced since the 1970s is the totally synthetic oxazolidinone antibacterial linezolid. Linezolid (Zyvox of Pfizer/Pharmacia) inhibits vancomycin-resistant strains of bacteria. The oxazolidinone antibiotics were discovered at DuPont, who announced their findings in 1987. Then, scientists at Upjohn started their program on this group and linezolid was approved in 2000 for use against MRSA. Pharmacia-Upjohn filed the patent application and today, Pfizer is the marketer of this useful new antibiotic. It possesses Gram-positive activity and lacks cross-resistance to every clinically significant resistance mechanism tested. It is active against VRE, MRSA, penicillin-resistant pneumococci, cephalosporin-resistant bacteria, multidrug-resistant Mycobacterium tuberculosis and M. avium, and some anaerobes. It is bacteriostatic, orally active, and also has some Gram-negative activity. Oxazolidinones have no structural relationship to other antimicrobials. They have a new mechanism of action, that is, interference with the initiation of translation. They inhibit protein synthesis in growing bacteria by binding to the 50S ribosomal subunit and inhibiting formation of the 70S ribosomal initiation complex. Many analogs have been made with increased Gram-positive and Gram-negative activity.