The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

Abstract

Quinolones are broad-spectrum synthetic antibacterial drugs first obtained during the synthesis of chloroquine. Nalidixic acid, the prototype of quinolones, first became available for clinical consumption in 1962 and was used mainly for urinary tract infections caused by Escherichia coli and other pathogenic Gram-negative bacteria. Recently, significant work has been carried out to synthesize novel quinolone analogues with enhanced activity and potential usage for the treatment of different bacterial diseases. These novel analogues are made by substitution at different sites--the variation at the C-6 and C-8 positions gives more effective drugs. Substitution of a fluorine atom at the C-6 position produces fluroquinolones, which account for a large proportion of the quinolones in clinical use. Among others, substitution of piperazine or methylpiperazine, pyrrolidinyl and piperidinyl rings also yields effective analogues. A total of twenty six analogues are reported in this review. The targets of quinolones are two bacterial enzymes of the class II topoisomerase family, namely gyrase and topoisomerase IV. Quinolones increase the concentration of drug-enzyme-DNA cleavage complexes and convert them into cellular toxins; as a result they are bactericidal. High bioavailability, relative low toxicity and favorable pharmacokinetics have resulted in the clinical success of fluoroquinolones and quinolones. Due to these superior properties, quinolones have been extensively utilized and this increased usage has resulted in some quinolone-resistant bacterial strains. Bacteria become resistant to quinolones by three mechanisms: (1) mutation in the target site (gyrase and/or topoisomerase IV) of quinolones; (2) plasmid-mediated resistance; and (3) chromosome-mediated quinolone resistance. In plasmid-mediated resistance, the efflux of quinolones is increased along with a decrease in the interaction of the drug with gyrase (topoisomerase IV). In the case of chromosome-mediated quinolone resistance, there is a decrease in the influx of the drug into the cell.

Keywords: analogues; gyrase; quinolones; resistance; topoisomerase IV.

Figure 1

Chemical structure of nalidixic acid.

Scheme 1

Metal-free oxidative intermolecular Mannich reaction for the synthesis of 2-arylquinone-4(1H)-ones from secondary amines and ketones [6].

Scheme 2

Site selective C-H alkynylation of Quinolones [22].

Scheme 3

Preparation of chiral 2-substituted 2,3-dihydro-4-quinolones through chiral phosphoric acid catalyzed intra-molecular aza-Michael addition reaction.

Scheme 4

Per-6-ABCD catalyzed asymmetric one-pot synthesis of 2-aryl-2,3-dihydro-4-quinolones using substituted aldehydes [24].

Scheme 5

Synthesis of 4-quinolones via palladium catalyzed carbonylative Sonogashira cross-coupling reaction [25].

Scheme 6

Metal free arylation of ethylacetoacetate with hypervalent diaryliodonium for the synthesis of 3-aryl-4(1H)-quinolones [26].

Scheme 7

Palladium catalyzed-oxidative annulation of acrylamide with strained arynes for the synthesis of quinolones [27].

Scheme 8

Synthesis of 2-quinolones through ruthenium catalyzed cyclization of anilides with substituted propiolates or acrylates [28].

Figure 2

Common analogues of quinolones used for the treatment of different diseases.

Figure 2

Common analogues of quinolones used for the treatment of different diseases.

Figure 2

Common analogues of quinolones used for the treatment of different diseases.

Figure 3

Quinolone-enzyme interaction [86].