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.

Evaluation of Machine Learning and Rules-Based Approaches for Predicting Antimicrobial Resistance Profiles in Gram-negative Bacilli from Whole Genome Sequence Data

“…No resistance genes to ciprofloxacin were identified by functional metagenomics, since the native quinolone targets in the expression strain provide dominant susceptibility even in the context of exogenous expression of alternative resistant targets (Naeem et al, 2016), and the qnr genes present in these genomes were insufficient to provide resistance on their own. Consistent with using gentamicin as our only aminoglycoside resistance selection, only aminoglycoside modifying enzymes specific to gentamicin were identified by functional metagenomics, though aminoglycoside modifying enzymes with other specificities were annotated in the genomes.…”

In vitro Antibacterial Activity of 7-Substituted-6-Fluoroquinolone and 7-Substituted-6,8-Difluoroquinolone Derivatives

“…Because of their exceptionally good diffusion, they act on infections with different locations (urinary tract, meningeal, respiratory, osteoarticular, urogenital) [1]. Fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase in gram-negative bacteria and topoisomerase IV in gram-positive bacteria.…”

“…Also, some antibacterial quinolones have unacceptable side effects. For example, trovafloxacin and grepafloxacin were recently removed due to their liver and cardiac toxicity, respectively [1]. …”

Calprotectin Complex Interactions with Phytoquinolines and New Target Binding Alternates Calprotectin complex and Phytoquinolines

“…Different derivatives are compared, analysed and these molecules are found to successfully exhibit pharmacological properties. [15][16][17][18][19][20][21] Carboxamide derivatives of quinoline control autoimmune disease, by targeting the S100 members, the calprotectin, especially through its binding to S100A9. A defined structureactivity relationship (SAR) emerged during the analysis of these interactions, and inhibitory interactions of RAGE, TLR4/MD2 , TNF-α.…”