Safety Concerns Surrounding Quinolone Use in Children
The fluoroquinolones are broad-spectrum antibiotics with particular activity Structure-activity relationship (SAR) studies of quinolone antibacterial agents showed . no arthropathies were observed in more than 1, children who received. Due to their broad spectrum of activity, fluoroquinolones are effective Christ W, Lehnert T. Structure-activity relationship of fluoroquinolones. J Med Microbiol. May;44(5) Quinolones: structure-activity relationships and future predictions. Tillotson GS(1). Author information.
Overview of FQs 1.
Classification Nalidixic acid, a first generation FQ, was initially introduced in for the treatment of urinary tract infections, and for more than 2 decades, it was used in children 3 months and older without restriction 2 - 4. Nalidixic acid was discovered accidentally by Lesher and coworkers as a by-product of the synthesis of the antimalarial compound chloroquine 4. This discovery led to the development of quinolone compounds, and fluorination of quinolone led to the introduction of second-generation of FQs like norfloxacin in and ciprofloxacin in Other second-generation FQs, like levofloxacin, followed soon thereafter.
The addition of the fluorine atom improves potency, enhances antimicrobial activity, and alters pharmacokinetic properties. Incorporating different substituents to various positions on the quinolone nucleus varies antimicrobial activity and alters FQ side-effect profiles 34 Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA replication.
Topoisomerase II is also a target for a variety of quinolone-based drugs. High activity against the eukaryotic type II enzyme is exhibited by drugs containing aromatic substituents at their C-7 positions. This modification, coupled with the constant action of the topoisomerase II in the bacterial cell, leads to DNA fragmentation via the nucleasic activity of the intact enzyme domains. Third- and fourth-generation fluoroquinolones are more selective for the topoisomerase IV ligase domain, and thus have enhanced gram-positive coverage.
For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria.
Systemic use of fluoroquinolone in children
However, there is debate concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells. Some compounds in this class have been shown to inhibit the synthesis of mitochondrial DNA. The use of several FQs have been severely restricted because of advers effects; clinafloxacin causing phototoxicity and hypoglycaemia, SPFX causing phototoxicity [ 62 ].
Grepafloxacin has been withdrawn from the market due to prolongation of the QTc interval. Drug interactions are limited and are infrequent between FQs and other antit-TB drugs [ 64 ], however FQ absorption may be reduced when co administered with antacids containing multivalent cations [ 6566 ]. The mechanism by which quinolones enter the bacterial cell is complex [ 67 ]. The physicochemical properties of quinolones hydrophobicity, charge or molecular mass are important factors for bacterial cell penetration and play a different role in Gram-negative and Gram-positive bacteria.
Increasing molecular mass and bulkiness of substituents at C-7 position hinder penetration of quinolones into Gram-negative bacteria through the porin channels, although hydrophobic molecules appear to enter via the lipopolysaccharide or across the lipid bilayer [ 68 ].
Gram-positive bacteria do not possess an outer membrane, therefore lacking outer membrane proteins and lipopolysaccharide. Intracellular accumulation observed in Gram-positive bacteria e.SAR of phenylethanolamine /SAR of sympathomimetics
The unique cell wall structure of mycobacteria is rich in long-chain fatty acids such as C60 to C90 mycolic acids [ 39 ]. Mycolic acids are covalently linked to the peptidoglycan-associated polysaccharide arabinogalactan.
Study of Antimicrobial Quinolones and Structure Activity Relationship of Anti-Tubercular Compounds
Moreover, mycobacterial porins, the water-filled channel proteins which form the hydrophilic diffusion pathways, are sparse [ 70 ]. A major porin of M. The mycobacterial cell wall functions as an even more efficient protective barrier than the outer membrane of gram-negative bacteria and limits the access of drug molecules to their cellular targets Table 2.
Classification on the basis of spectrum of activity. Structure-activity relationship The minimal quinolone structure consists of a bicyclic system with a substituent at position N-1, a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6 in case of FQs Figure 1 and a substituent often nitrogen heterocycle moiety at the C Normally in position 2 there are no substituents, various 1-methylalkenyl-4 1H quinolones have been investigated as anti-TB agents [ 7273 ].
The DNA gyrase is most likely the only target of quinolone in M.
The DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against M. Some quinolones showed high inhibitory activity against M. Structure activity relationship SAR showed that C-8 with or lacking a substitution, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are advantageous structural features in targeting M.
The quinolones that showed high potency against M. Compounds grepafloxacin, gemifloxacin, TVFX, and the des[ 6 ] FQ garenoxacin with high activity against pneumococci showed only moderate activity against M.
In contrast to its effects against pneumococci, the presence of a group at C-5 [ 75 ]. Moreover, the presence of a naphthyridone core N-8 in gemifloxacin, which has the lowest MIC against gram-positive bacteria, seems adverse effect for a interaction with M.
Similarly, the naphthyridones tosufloxacin and enoxacin, were only moderately active [ 76 - 84 ]. The substituent at N-1 and C-8 positions should be relatively small and lipophilic to enhance self-association.
While at C-6 and C-7 positions at fluorine atom and amino group, respectively, appear to be the best. In particular fluorine atom at C-6 improves cell penetration and gyrase affinity [ 6685 ]. The nature of substituent at C-7 position has a great impact on potency, spectrum, solubility and pharmacokinetics.
Almost all quinolones have nitrogen heterocycles linked to this position through the heterocyclic nitrogen, extensively investigated are piperazinyl and its 4-substituted derivatives [ 86 ].
The resulst revealed that usually the increase of lipophilic character of the side chain at C-7 improves the anti-TB activity, without inducing cytotoxicity as demonstrate for balofloxacin ethylene isatin derivatives [ 87 ]. Furthermore, with regard to the substituent at N-1 position, studies confirm that the anti-TB activity is higher for the cyclopropyl and tert-butyl goup than for the 2,4-difluorophenyl and others groups [ 8990 ]. Ciprofloxacin and gatifloxacin 7-substituted derivative.
Extensive SAR study showed that an increase in the activity of a given quinolone against gram-positive bacteria does not necessarily lead to increased activity against M. ABT was also more potent than TVFX and CPFX against most quinolone-susceptible pathogens responsible for respiratory tract, urinary tract, bloodstream, and skin infections and against anaerobic pathogens. It was significantly more active than other quinolones against quinolone-resistant gram-positive strains.
Furthermore ABT was active against Chlamydia trachomatis, indicating good intracellular penetration. However the activity of ABT against M. The HSR is a newly synthesized quinolone with superior activity against gram-positive cocci [ 89 ]. Conclusion Quinolines are second-line anti-TB drugs, since their use in TB treatment still remains controversial [ 94 ]. On the contrary, they are suggested and recommended in managing MDR-TB, due to the fact that they have a broad and potent spectrum of activity and can also be administered orally, giving a better chance of cure and preventing the development and spread of further resistance [ 95 ].
However, quinolones remain one of the most widely prescribed antibiotics. In conclusion, we can confirm that in general quinolones are particularly adapted to be used as antitubercular agents. The history of quinolones In Fluoroquinolone Antibiotics. Fluoroquinolones tuberculosis and resistance. Fluoroquinolone resistance in patients with newly diagnosed tuberculosis.
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