Monday, 29 September 2014

Pharmacology and chemistry of quinolones: Broad spectrum antibiotics

Quinolones are synthetic broad spectrum antimicrobial agents. Older quinolones were active against mainly gram negative strains. Quinolones contain N-1-alkylated 3-carboxy pyrid-4-one ring fused to another aromatic ring.
·         Fluroquinolones are inactive in acidic pH and contraindicated in pregnancy as they cause cartilage damage.


Classification of Quinolones:

Classification of Quinolones



Mechanism of Action of quinolones:


·         Quinolones Inhibit DNA gyrase of gram negative and topoisomerase IV in gram positive bacteria.
·         DNA gyrase has two subunits (Subunit A & B) and performs basically three functions:
i)                    Nicking of double stranded DNA (subunit A). 
ii)                   Negative recoiling when the two strands separate to replicate and transcript (subunit B).
iii)                 Resealing (subunit A).
·         Fluroquinolones inhibits subunit A of DNA gyrase.
·         Whereas, function of topoisomerase IV is to preform nicking and separation of daughter DNA after replication.
·         Human contains topoisomerase II which has least affinity for quinolones.

Drug interactions of quinolones:

·         Quinolones increases the plasma con. Of theophylline, Caffeine and warfarin.
·         Quinolones with NSAIDs may increase CNS toxicity.


Structure activity relationship of quinolones:

SAR of Quinolones

·         Basic pharmacophore is Carboxy-4-pyridone nucleus.
·         Reduction of 2,3 double bond reduces activity.
·         Fluorine at C-6 increases lipophilicity hence drug penetration in bacterial cell wall and ultimately increased DNA gyrase activity.
·         Fluorine at C-8 increases absorption but also photo toxicity.
·         Heterocyclic substituent at C-7: Piperazinyl (Ciprofloxacin) and Pyrrolinyl {Moxifloxacin) increases activity for gram negative strain.
·         Piperazinyl also responsible for CNS side effect at it also bind with GABA.
·         Alkyl substituent at piperazinyl reduces CNS side effects.
·         Cyclopropyl substituents at N-1: Increases activity against mycoplasma chlamydia & Legionella.
·         Third ring to nucleus: Ofloxacin (asymmetric C at C-3’) (S)-(-) isomer is more potent.


Adverse effects of quinolones:

1)      Cartilage damage (Before 18 years).
2)      CNS side effects ( Seizures)

3)      First three trimesters: Haemolytic anaemia & acidosis.

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