Agui H, Mitani T, Izawa A, Komatsu T, Nakagome T. Studies on quinoline derivatives and related compounds. 5. Synthesis and antimicrobial activity of novel. Expedited SAR study of an mGluR5 antagonists: generation of a focused library . Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor . Discovery of inhibitors of plasminogen activator inhibitor Structure–activity study of . Structure–activity relationship study of pyridazine derivatives as glutamate .. Synthesis and structure–activity relationship of 4-quinolone carboxylic acid . Corrigendum to “Synthesis and antihistamine evaluations of novel loratadine.
Effects of norfloxacin on DNA metabolism in Pseudomonas aeruginosa. In vitro activity of difloxacin hydrochloride AA, and cefixime CL ,; FK against selected genital pathogens. In vitro activity of Roa new fluorinated 4-quinolone. Synthesis and structure-activity relationships of novel arylfluoroquinolone antibacterial agents. Synthesis and biological activity of benzothiazolo[3,2-a]quinolone antibacterial agents. Enantiomers of 1-ethyl[3-[ ethylamino methyl]pyrrolidinyl]-6,8-difluoro-1,4- dihydrooxoquinoline-carboxylic acid: New structure-activity relationships of the quinolone antibacterials using the target enzyme.
The development and application of a DNA gyrase assay. New quantitative structure-activity relationships at N1 for the quinolone antibacterials. A new synthesis of 7H-pyrido[1,2,3-de][1,4]benzoxazine derivatives including an antibacterial agent, ofloxacin.
Chem Pharm Bull Tokyo Oct;34 Geneva, Switzerland, July In-vitro and in-vivo potency of five new fluoroquinolones against anaerobic bacteria. Activity of E, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats.
Structure-activity relationships of the fluoroquinolones.
Monocyclic and tricyclic analogs of quinolones: Synthesis, absolute configuration, and antibacterial activity of 6,7-dihydro-5,8-dimethylfluorooxo-1H,5H- benzo[ij]quinolizinecarboxylic acid. Difloxacin metabolism and pharmacokinetics in humans after single oral doses. Comparative antibacterial activities of temafloxacin hydrochloride A and two reference fluoroquinolones.
Isolation and characterization of norfloxacin-resistant mutants of Escherichia coli K Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa. Genetic and biochemical characterization of norfloxacin resistance in Escherichia coli.
There was a problem providing the content you requested
Recent advances in pharmaceutical chemistry. Renal disease, hemodialysis, and steroid use may be predisposing factors [ 28 ]. The use of FQs in children has been contraindicated for this reason. However, children with cystic fibrosis given CPFX, norfloxacin, and nalidixic acid have had few, and reversible, joint symptoms [ 30 ].
Leukopenia, eosinophilia, and mild elevations in serum transaminases occur rarely. Quinolones probably should be used only with caution in patients treated with amiodarone and quinidine, procainamide as antiarrhythmics Table 1. Approved clinical uses for selected fluoroquinolones.
Quinolones and Chemotherapy Quinolones are classified in four generations. Most recent FQs are being evaluated as potential anti-TB drugs, also for the shorten TB treatment duration, one of the major strategies for TB control [ 32 ].
Fluorine-containing nalidixic acid derivatives, the FQs, were introduced into clinical practice in the s [ 31 ]. Norfloxacin, the first of a new generation of FQ are antibacterial activity [ 34 ]. Substitutions of the FQ molecule resulted in the development of CPFX, a widely used broad spectrum antimicrobial agent [ 35 ].
Several modifications of the FQ structure have been attempted in order to develop new expanded antimicrobial agents with improved pharmacokinetic profiles, decreased resistant mutants, reduced adverse effects, and improved efficacy [ 3637 ]. Last-generation FQs share a broad-spectrum antimicrobial activity covering aerobic and anaerobic Gram-positive and Gram-negative bacteria as well as mycobacteria M. Fluoroquinolones are widely used for the treatment of infections of the respiratory, gastrointestinal and urinary tracts, sexually transmitted diseases, skin and soft tissue infections and chronic osteomyelitis [ 4041 ].
New FQs are in various phases of clinical development like tosufloxacin, fleroxacin, clinafloxacin, gemifloxacin, rufloxacin, enrofloxacin, difloxacin, amifloxacin, iloxacin, temafloxacin, nadifloxacin, grepafloxacin, balofloxacin, pazufloxacin, prulifloxacin, sitafloxacin, garenoxacin, olamufloxacin [ 4243 ].
Appreciable efficacies of FQs have also been demonstrated against both M. Many new FQs indicated for the treatment of respiratory tract infections show excellent activity against MAC isolates [ 4849 ]. The value of FQs in the treatment of TB infections may be attributed to the good penetration into infected macrophages where they exert antibacterial activity [ 57 ].
Selected quinolones, on the intracellular activity against M. Certain drugs, such as rifampin, rifabutin, isiniazid, clofazimine, and some FQs, strongly or moderately reduced the anti-MAC activity [ 59 ]. The major problem linked with the use of FQs is the increased incidence of FQ- resistant strains of M.
Pharmacokinetics The common adverse effects associated with the use of FQs are gastrointestinal disturbances, nervous system complaints dizziness, headacheand allergic reactions skin rashes and pruritus [ 6061 ]. 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. 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. 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 ].
Structure-activity relationships of the fluoroquinolones.
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. N Engl J Med. World Health Organization HIV infection associated tuberculosis: Clin Infect Dis, ; Accelerated course of human immunodeficiency virus infection after tuberculosis.
Activity in vitro of the quinolones. In Quinolone Antimicrobial Agents, 2nd edn. The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. Medical Letter Gatifloxacin and moxifloxacin: Med Lett Drugs Ther.
Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump. Management of fluoroquinolone resistance in Pseudomonas aeruginosa: Outcome of monitored use in a referral hospital.
Int J Antimicrob Agents. Drlica K, Zhao X. DNA gyrase topoisomerase IV and the 4-quinolones. Microbiol Mol Biol Rev. Engineering the specificity of antibacterial fluoroquinolones: New Engl J Med.
III Comparison of one- or two-dose ciprofloxacin with standard 5-day therapy A randomized blinded trial. V Comparison of azithromycin and ciprofloxacin A double-blind randomized controlled trial. Ann Intern Med ; Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada Canadian Bacterial Surveillance Network.
Ofloxacin versus parenteral therapy for chronic osteomyelitis. Treatment of tularemia with ciprofloxacin. Recognition and management of anthrax: Improved safety profile of newer fluoroquinolone. Antagonism of GABA receptors by 4-quinolones.