SAR of Quinolones

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Chapter: Medicinal Chemistry : Quinolone Antibacterials

The optimum substituents at position 1 appear to be ethyl, butyl, cyclopropyl, and difluorophenyl, and these substituents have resulted in potent compounds.


SAR of Quinolones


1. Substituent at N-1 position: The optimum substituents at position 1 appear to be ethyl, butyl, cyclopropyl, and difluorophenyl, and these substituents have resulted in potent compounds. Addition of a fluorine atom into the N-1 cyclopropyl group or the 1-butyl substituent resulted in compounds with overall improved activity against gram-positive bacteria.

2. The simple replacement of C-2 hydrogen has been generally disadvantageous (e.g. C-2 methyl or hydroxy groups); however, some derivatives containing a suitable C-1, C-2 ring have shown to possess notable activity.


3. The carboxy functions at position: Modification of C-3 carboxylic acid group leads to decrease in antibacterial activity. However, replacement of C-3 carboxylic group with isothiazolo group afforded most active isothiazolo quinolone, which has been 4–10 times greater in in vitro antibacterial activity than ciprofloxacin. The isothiazolo system possesses aromatic character and the nitrogen proton is very acidic and can be considered as an carboxylic acid mimic, whereas other groups, such as sulphonic acid, phosphonic acid, tetrazole as well as derivatization, as an ester lead to loss of antibacterial activity.


4. The C-4-oxo group of the quinolone nucleus appears to be essential for antibacterial activity. Replacement with 4-thioxo or sulphonyl group leads to a loss of activity.

5. The incorporation of a group at the C-5 position has proven beneficial in terms of antibacterial activity. The order of activity is NH2: CH3>F, H>OH, or SH, SR.

6. The incorporation of a fluorine atom at the C-6 position of the quinolone is monumental. The order of activity is F>Cl, Br, CH3>CN.

7. The introduction of a piperazine moiety at the C-7 position is essential. Other aminopyrrolidines also are compatible for activity.


8. In general, a C-8 fluoro substituent offers good potency against gram-negative pathogens, while a C-8 methoxy moiety is active against gram-positive bacteria. The order of activity is F, Cl, OCH3>H, CF3>methyl, vinyl, propargyl.

9. A halogen (F or Cl) at the C-8 position improves oral absorption.

10. Linking of N-1 group to the C-8 position with oxazine ring leads to active oflaxacin.

 

Uses: Fluoroquinolones are used to treat upper and lower respiratory infections, gonorrhoea, bacterial gastroenteritis, skin soft tissue infections, urinary tract infections, bone and joint infections, and against tuberculosis.

 

ADVERSE EFFECTS

The most common adverse reactions are nausea, headache, and dizziness. Some CNS problems, such as hallucination, insomnia, and visual disturbances can occur. Some side effects of the quinolones are class effects and cannot be modulated by molecular variation. Most of the fluoroquionolones produce photosensitivity reactions and cause convulsions particularly in concurrent administration of NSAID fenopofen. Increasing steric bulk through alkylation ameliorates these effects. Phototoxicity is determined by the nature of the 8-position substituent with halogen causing the greatest photoreaction while hydrogen and methoxy show little light produced toxicity. These drugs are not recommended for use in pretubertal children or pregnant women.

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