Levofloxacin: Synthesis, Uses, Mechanism of Action, Dosage and Side Effects
Levofloxacin is a broad-spectrum fluoroquinolone antibiotic and the active S-(-) isomer of the racemic drug ofloxacin. Developed by Daiichi Seiyaku and patented in 1987, it was first approved by the FDA in 1996. It is now on the World Health Organization's List of Essential Medicines. Levofloxacin is used for treating a wide range of bacterial infections, including pneumonia, urinary tract infections, skin infections, and certain types of anthrax and plague.
Synthesis of Levofloxacin
Synthesis of Levofloxacin takes place in the following steps;
Step 1: Alkylation and Reduction: The synthesis starts with the reaction of 2,4-difluoro-4-hydroxy-3-nitrobenzene with allyl chloride in the presence of K2CO3 and KI in acetone, forming an ether linkage. The nitro group is then reduced to an amine using H2 and Raney nickel.
Step 2: Cyclization: The aromatic amine intermediate reacts with diethyl ethoxymethylenemalonate at 130−140°, forming a quinolone ring structure through a cyclization reaction.
Step 3: Ring Closure and Hydrolysis: The intermediate then undergoes a ring-closure reaction using polyphosphoric acid (PPE) at 140−145°C, forming the core bicyclic quinolone ring system. This is followed by hydrolysis of the ethyl ester group using concentrated HCl and acetic acid (AcOH) to yield the carboxylic acid intermediate.
Step 4: Piperazine Ring Attachment: The carboxylic acid intermediate reacts with piperazine in dimethyl sulfoxide (DMSO). The piperazine group is attached to the quinolone ring, forming ofloxacin, a racemic mixture.
Step 5: Resolution: The final step involves separating the racemic ofloxacin mixture to isolate the biologically active enantiomer, levofloxacin. This is achieved through methods like optical, enzymatic, or crystallization resolution.
Medical Uses of Levofloxacin
Levofloxacin is a versatile antibiotic with applications in treating:
- Treats respiratory tract infections (pneumonia, bronchitis), sinus infections, skin infections, urinary tract infections, prostatitis, and abdominal infections.
- Can be used in cases of anthrax exposure and plague.
- Sometimes prescribed for infections when other antibiotics are unsuitable due to resistance or patient allergies.
Mechanism of Action of Levofloxacin
Levofloxacin is a bactericidal agent that works by targeting key bacterial enzymes: DNA gyrase and topoisomerase IV. These enzymes are crucial for bacterial DNA replication, transcription, and repair. By inhibiting their function, levofloxacin prevents bacteria from multiplying and ultimately kills them. It is highly effective against both Gram-positive and Gram-negative bacteria, with enhanced activity against pathogens like Streptococcus pneumoniae.
Dosage and Pharmacokinetics of Levofloxacin
- Available in oral tablets (250 mg, 500 mg, 750 mg), oral solution, and intravenous forms.
- Both oral and IV preparations provide similar systemic exposure, making them interchangeable.
- Peak plasma concentration is reached within 1.5 hours after intake; the elimination half-life is about 6–8 hours.
- The drug is largely excreted unchanged via urine (87%).
Side Effects and Warnings of Levofloxacin
- Common Side Effects: Nausea, diarrhea, headache, dizziness, and trouble sleeping.
- Serious Risks: Tendon rupture, nerve damage, seizures, psychosis, low blood sugar, aggravation of muscle weakness in myasthenia gravis, and increased risk of sunburn.
Due to the risk of these severe and potentially irreversible side effects, the FDA recommends reserving systemic levofloxacin for patients who have no alternative treatment options for certain uncomplicated infections like acute bacterial sinusitis, uncomplicated urinary tract infections, and acute bacterial exacerbation of chronic bronchitis.