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Synthetic antibacterial agents

Chloramphenicol �First, isolated from streptomyces bacteria in 1947. �Due to its simple structure, nowadays it is widely produced in large scale by chemical synthesis from Pnitroacetophenone. �It has a bacteriostatic action, inhibiting bacterial protein biosynthesis…. Believed to be through inhibiting the elongation step. �It has a broad spectrum of activity, but because of its serious systemic toxicity (aplastic anemia), it is mainly used topically for skin and eye infections.

Chloramphenicol �Active on both gram +ve and gram –ve bacteria, even on penicillin resistant strains such as H. influenza, N. meningititis and S. pneumonia. �It has a good penetration to CNS… used in meningitis. �Not recommended in UTI (why? )… only 5 -10% of the unmetabolized chloramphenicol is excreted in urine. �Bacteria became resistant to chloramphenicol through the production of chloramphenicol acyltransferase which acylate the OH group at C 1 and C 3 to the inactive esters.

Metabolism of Chloramphenicol

SAR of Chloramphenicol �P-nitro group can be replaced by other aryl ring or oxygenated functional group without great loss in activity. �Phenyl ring can accept multi-substitutions. �Conversions of 1 -OH to keto group causes appreciable loss inactivity.

Chloramphenicol esters �They have better physicochemical properties than Chloramphenicol which has both bitter taste and bad water solubility.

Quinolones antibacterial agents �Nalidixic acid is the lead compound for this group. �According to the heterocyclic core can be divided into: �Naphthyridines: nalidixic acid and enoxacin. �Quinolines: norfloxacin, ciprofloxacin, lemofloxacin. �Cinnolines: Cinoxacin

Quinolones antibacterial agents �Spectrum of activity: �Highly active against urinary tract pathogens such as E. coli, Klebsiella, Citrobacter, proteus as well as salmonella and shigella. �Most except fluoroquinolones are not active on P. aeruginosa and H. influenza. �Inactive on anaerobic and gram +ve bacteria. �Pharmacokinetics: �They have good oral bioavailability. �They reach urine in enough concentration to be effective in UTI (>40%).

Quinolones antibacterial agents �Mechanism of action: Inhibit DNA synthesis by inhibiting DNA gyrase (topoisomerase-II) which is important for DNA supercoiling. �Transport into bacterial cell: mainly through the porin channels of the gram –ve bacteria. �Mechanisms of bacterial resistance: �Mutation in porin channels. �Energy dependant efflux mechanism.

SAR of Quinolones �The carboxylic acid at C 3 is essential for activity. �Pyridone ring must be annulated with aromatic ring such as in Naphthyridine, Quinolines and Cinnolines. �Isosteric replacement of nitrogen for C 2, C 5, C 6 or C 8 resulted in retained activity. �Substitution at C 2 greatly reduces or abolishes activity. �Positions 5, 6, 7 and 8 can be substituted for better efficacy

SAR of Quinolones �Positions 5, 6, 7 and 8 can be substituted for better efficacy: �Piperazine ring and 3 -aminopyrrolidine at C 7 enhances activity, mainly against P. aeruginosa. �Fluorine atom at C 6 also improved activity (Fluoroquinolones). �Alkyl substitution on C 1 improves activity (but small alkyl or aryl group). �Ring condensation at 1 -8, 5 -6, 6 -7 and 7 -8 also lead to better activity.

Fluoroquinolones �They are 6 -fluoro-7 -piperazinoquinolones derivatives. �They exhibit extended spectrum of activity that covers most of gram +ve and gram –ve bacteria especially P. aeruginosa. �Members: �Ciprofloxacin. �Norfloxacin. �Ofloxacin. �Pefloxacin. �Lomefloxacin. �Enofloxacin. �Levofloxacin.

Chemical structure of Fluoroquinolones �Have an acidic (3 -carboxylic acid) and basic (piperazinyl) group, this makes these compounds present as zwitterionic species at physiological p. H. �Like tetracyclines, they have chelating properties due to the presence of β-diketo structure. They can form stable, insoluble metal complexes with di and trivalent metal ions: �They should not be given along with antacids and mineral supplements. � formation of this chelate will reduce the oral availability of these agents.

Chemical structure of Fluoroquinolones �Fluorine atom at C 6 increases potency against gram – ve bacteria. �The piperazinyl group at C 7 improves antipsuedomonal activity of Fluoroquinolones. �Chelation also has another –ve effect: the possibility to chelate with urine ions (Mg++ and Ca++) which leads to crystalluria Renal failure sometimes.

Enoxacin �Well absorbed following oral administration (90%). �Well distributed through the body… reaches kidney, prostate and cervix. �Used mainly in prostatitis. Ciprofloxacin � 40 -50% excreted unchanged in urine. �Highly distributed to all body fluids including CS fluid. �Highly potent against gram –ve especially P. aeruginosa (why? ). �Used in gastroenteritis, skin, soft tissues (bone and joints) infections and UTI.

Ofloxacin �Has 1, 4 -oxazine ring. �Has better penetration to CNS than ciprofloxacin (why? ). �The structure has asymmetric carbon atom, normally ofloxacin is given as racemate, although the 3 S(-) isomer is 125 x more active than the 3 R(+) isomer. �Recently the 3 S(-) isomer (Levofloxacin) has been prepared and now marketed instead of ofloxacin which is more potent (Chiral switching phenomenon)

Lomefloxacin �Has longer duration of action (t 1/2 =7 -8 hrs), this is believed to be due to: �Excellent tissue distribution. �Efficient renal reabsorption. �The only one that is given once daily. �It has an excellent oral bioavailability (98%). �Mainly used in acute bronchitis. �High incidence of phototoxicity due to the presence of two fluorine atoms. �Phototoxicity: is the formation of highly reactive oxygen radicals due to the exposure to light.

Sparfloxacillin �Higher potency against gram +ve Staphylococcus and streptococcus bacteria. �More active on anaerobic bacteria and Chlamydia. �Long t 1/2 (= 18 hrs) �Has the lowest incidence for phototoxicity.

New generation fluoroquinolones �Gemifloxacin: �is an oral broad-spectrum quinolone antibacterial agent. �Active against both gram +ve and gram –ve bacteria except P. aeruginosa. �used in the treatment of chronic bronchitis and mild-to -moderate pneumonia. �Has a protein binding of 60 -70%. �Only 5 -10% of the drug will be metabolized in the body to give the N-acetyl and the glucuronide conjugate.

New generation fluoroquinolones �Moxifloxacin: �Considered a fourth generation quinolones. �Given orally, parenterally and as eye drops for treatment of conjunctivitis (Bayer). � Uses: Chronic bronchitis. � Acute bacterial sinusitis. � Pneumonia. � Skin infections. � � 20% excreted unchanged in urine and 25% in feces. �More than 50% of the drug metabolized to the sulfate and glucuronide conjugates.