The wonder drug --Quinolones.

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Quinolones , The Quinolone are class of antimicrobial agents that was not isolated from living organisms but, rather, was synthesized by chemists. They are a group of synthetic broad spectrum antibacterial drugs that target DNA Synthesis. The prolific development of the Quinolones began in 1962, when Lesher et al. made the accidental discovery of nalidixic acid as a by-product of the synthesis of the antimalarial compound chloroquine.

Transcript of The wonder drug --Quinolones.

  • The Quinolones: Past, Present and FutureThe Quinolones: Past, Present and Future
  • The Past.The Past. The Quinolone are class of antimicrobial agents thatThe Quinolone are class of antimicrobial agents that was not isolated from living organisms but, rather,was not isolated from living organisms but, rather, was synthesized by chemists.was synthesized by chemists. They are a group of synthetic broad spectrumThey are a group of synthetic broad spectrum antibacterial drugs that target DNA Synthesis.antibacterial drugs that target DNA Synthesis. The prolific development of the Quinolones began inThe prolific development of the Quinolones began in 1962, when Lesher et al. made the accidental1962, when Lesher et al. made the accidental discovery of nalidixic acid as a by-product of thediscovery of nalidixic acid as a by-product of the synthesis of the antimalarial compound chloroquine.synthesis of the antimalarial compound chloroquine.
  • The Past.The Past. Nalidixic acid became the lead compound forNalidixic acid became the lead compound for medicinal chemists for structural modificationsmedicinal chemists for structural modifications to get many newer fluoroquinolones in orderto get many newer fluoroquinolones in order to get rid of its three major shortcomings.to get rid of its three major shortcomings. Narrow spectrum covering Gr (-ve) organismsNarrow spectrum covering Gr (-ve) organisms onlyonly Achieves inadequate tissue levels forAchieves inadequate tissue levels for systematic infections andsystematic infections and Bacterial resistance development.Bacterial resistance development.
  • The Past.The Past. This discovery led to the development of a library ofThis discovery led to the development of a library of quinolone compounds, especially the newerquinolone compounds, especially the newer quinolones in clinical use at the present time.quinolones in clinical use at the present time. Fluoroquinolones are the derivatives of quinolonesFluoroquinolones are the derivatives of quinolones which are fluorinated at C-6 position of the quinolonewhich are fluorinated at C-6 position of the quinolone ring. They are broad-spectrum bactericidal agentsring. They are broad-spectrum bactericidal agents inhibiting DNA synthesisinhibiting DNA synthesis They act on two enzymes involved in DNA synthesis:They act on two enzymes involved in DNA synthesis: DNA gyrase and topoisomerase IV and therebyDNA gyrase and topoisomerase IV and thereby block DNA replication and transcription, leading toblock DNA replication and transcription, leading to cell deathcell death
  • The Past.The Past. The various derivatives of fluoroquinoloneThe various derivatives of fluoroquinolone have varying levels of activity depending onhave varying levels of activity depending on the various groups attached at differentthe various groups attached at different positions.positions. Generating a derivative with increased activityGenerating a derivative with increased activity helps to reduce the Minimum Inhibitoryhelps to reduce the Minimum Inhibitory Concentration (MIC), thereby reducing theConcentration (MIC), thereby reducing the possibility of developing resistance to it.possibility of developing resistance to it.
  • The PresentThe Present Two main classifications for fluoroquinolones based onTwo main classifications for fluoroquinolones based on chemical structure and biological properties respectively haschemical structure and biological properties respectively has been described by Bryskier & Chantot , which logicallybeen described by Bryskier & Chantot , which logically embraces the majority of active compounds known till date.embraces the majority of active compounds known till date. Differences in the in-vitro activity of the fluoroquinolonesDifferences in the in-vitro activity of the fluoroquinolones against gram positive and gram negative organisms primarilyagainst gram positive and gram negative organisms primarily form the basis of their biological classification, as shown inform the basis of their biological classification, as shown in table 1.table 1. The first generation being the most narrow and the subsequentThe first generation being the most narrow and the subsequent ones having an increase in spectrum of activity and on theones having an increase in spectrum of activity and on the novelty and complexity of the structures of quinolones.novelty and complexity of the structures of quinolones.
  • Table one .Table one . GenerationGeneration DrugsDrugs AntibacterialAntibacterial spectrumspectrum FirstFirst Nalidixic acidNalidixic acid aerobic, gram-aerobic, gram- negativebacteria.negativebacteria. SecondSecond NorfloxacinNorfloxacin CiprofloxacinCiprofloxacin EnoxacinEnoxacin FleroxacinFleroxacin LomefloxacinLomefloxacin OfloxacinOfloxacin LevofloxacinLevofloxacin RufloxacinRufloxacin antimicrobial activityantimicrobial activity against aerobic gram-against aerobic gram- positive bacteria andpositive bacteria and improved activity againstimproved activity against gram-negative bacteriagram-negative bacteria
  • Table oneTable one GenerationGeneration DrugsDrugs Antibacterial spectrumAntibacterial spectrum ThirdThird TosufloxacinTosufloxacin GatifloxacinGatifloxacin GemifloxacinGemifloxacin TemafloxacinTemafloxacin GrepafloxacinGrepafloxacin gram-positive bacteria,gram-positive bacteria, particularly pneumococci; theyparticularly pneumococci; they also had good activity againstalso had good activity against anaerobicanaerobic FourthFourth Besifloxacin,ClinafloxacinBesifloxacin,Clinafloxacin Garenoxacin, GGarenoxacin, Gemifloxacinemifloxacin MoxifloxacinMoxifloxacin GatifloxacinGatifloxacin SitafloxacinSitafloxacin Trovafloxacin/AlatrofloxacinTrovafloxacin/Alatrofloxacin PrulifloxacinPrulifloxacin anaerobes and increased activityanaerobes and increased activity against pneumococciagainst pneumococci FifthFifth DelafloxacinDelafloxacin
  • StructureStructure All fluoroquinolones have a basicAll fluoroquinolones have a basic 4-quinolone structure, with a4-quinolone structure, with a fluorine atom at C-6 position.fluorine atom at C-6 position. Differences between the variousDifferences between the various fluoroquinolones are usually duefluoroquinolones are usually due to various groups that are attachedto various groups that are attached at positions 1, 5, 7 and 8.at positions 1, 5, 7 and 8. The addition of specificallyThe addition of specifically selected substituents at these keyselected substituents at these key positions on the quinolonepositions on the quinolone nucleus made it possible to targetnucleus made it possible to target specific groups of bacteria and tospecific groups of bacteria and to improve theimprove the pharmacokinetics ofpharmacokinetics of the earlier quinolone compoundsthe earlier quinolone compounds
  • .Structure.Structure Some of the key structural modifications are :Some of the key structural modifications are : addition of a fluorine atom at position C-6, which increased DNA gyraseaddition of a fluorine atom at position C-6, which increased DNA gyrase inhibitory activity, facilitated penetration into the bacterial cell, andinhibitory activity, facilitated penetration into the bacterial cell, and provided activity against staphylococci.provided activity against staphylococci. The addition of a piperazine group at position C-7 provided the greatestThe addition of a piperazine group at position C-7 provided the greatest activity against aerobic gram-negative bacteria and increased the activityactivity against aerobic gram-negative bacteria and increased the activity against both staphylococci andagainst both staphylococci and PseudomonasPseudomonas species and also increasedspecies and also increased the elimination half-life and improved bioavailability.the elimination half-life and improved bioavailability. The addition of a second fluorine group at position C- 8 resulted inThe addition of a second fluorine group at position C- 8 resulted in increased absorption and a longer elimination half-life but also increasedincreased absorption and a longer elimination half-life but also increased phototoxicity.phototoxicity. In addition, increased activity againstIn addition, increased activity against MycoplasmaMycoplasma andand ChlamydiaChlamydia speciesspecies was achieved by adding an amino group at C-5 and a fluorine group at C-8was achieved by adding an amino group at C-5 and a fluorine group at C-8 to quinolone compounds that possessed a cyclopropyl group at N-1 asto quinolone compounds that possessed a cyclopropyl group at N-1 as seen in ciprofloxaxin, sparfloxacin and gatifloxacin.seen in ciprofloxaxin, sparfloxacin and gatifloxacin.
  • .Structure.Structure The most recent key modification was theThe most recent key modification was the observation that the addition of a methoxyobservation that the addition of a methoxy group, instead of a halide, at the C-8 positiongroup, instead of a halide, at the C-8 position specifically targets both topoisomerase II andspecifically targets both topoisomerase II and IV, which also may decrease the possibility ofIV, which also may decrease the possibility of the development of resistance to quinolones .the development of resistance to quinolones . Of the currently available