Quinolones PDF - Medicinal Chemistry III

Medicinal Chemistry III Synthetic Antibacterials: Quinolones CHAPTER 7: SYNTHETIC ANTIBACTERIAL AGENTS: QUINOLONES Sam Dawbaa, Pharm. Chem. Ph.D. A. MECHA...

Medicinal Chemistry III Synthetic Antibacterials: Quinolones CHAPTER 7: SYNTHETIC ANTIBACTERIAL AGENTS: QUINOLONES Sam Dawbaa, Pharm. Chem. Ph.D. A. MECHANISM OF ACTION. The quinolones are rapidly bactericidal because of the inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV (key bacterial enzymes in the conformation of DNA) → makes a cell’s DNA inaccessible → leads to cell death. Quinolones inhibit these essential enzymes to different extents → differences in the spectrum of activity. Topoisomerase IV is more important to some gram- positive organisms, and DNA gyrase seems more important to some gram-negative organisms. Human cells use topoisomerase II analogue which does not bind quinolones at normal doses → no bactericidal effect on human cells. B. CLASSES & THERAPEUTIC USES. Quinolones (sometimes are indicated as fluoroquinolones according to the 6-fluoro substitution) in general can be classified according to the main nucleus ring into: a. Quinolones e.g., ciprofloxacin, norfloxacin, lomefloxacin b. Naphthyridines e.g., nalidixic acid, enoxacin c. Cinnolines e.g., cinoxacin They also classified according to the therapeutic application into four generations as illustrated in the following table. a. First generation: nalidixic acid & cinoxacin for UTIs. b. Second generation: Ciprofloxacin (UTIs, URTIs, bone infections, septicemia, staphylococcal and pseudomonal endocarditis, meningitis, typhoid, and anthrax infections) & norfloxacin (UTIs, prostatitis, gonorrhea). c. Third generation: levofloxacin, gatifloxacin, and gemifloxacin. They are used for bacterial exacerbation of chronic bronchitis and community-acquired pneumonia in addition to the uses of ciprofloxacin. d. Fourth generation: moxifloxacin (wider spectrum to include Bacteroides fragilis). 37  Medicinal Chemistry III Synthetic Antibacterials: Quinolones C. RESISTANCE. 1. Mutations in genes (gyrA and gyrB) that encode for the quinolone target protein, DNA gyrase, and genes (parC and parE) that encode for topoisomerase IV. 2. Efflux. 3. Decrease in outer membrane permeability (QSAR revealed that logP of quinolones is inversely proportional to bacterial uptake in G-ve bacteria, and logP is directly proportional to the uptake by G+ve bacteria). D. SYNTHETICAL APPROACH. E. ADVERSE EFFECTS & PHARMACOKINETICS. Adverse effects of quinolones: 1. Tendonitis & tendon rupture (black box warning) → not used in myasthenia gravis. 2. Phototoxicity. 3. Proconvulsive action (specially with NSAIDs). Other CNS SE: hallucinations, insomnia & visual disturbances. 4. Joint erosion in animals → not used under 18 & during pregnancy (in 1st trimester causes metabolic acidosis & hemolytic anemia). 5. Anorexia, diarrhea, abdominal pain, vomiting. 6. Cautious use with theophylline (increased activity) & antiarrhythmics (↑QT →torsades de pointes) 38  Medicinal Chemistry III Synthetic Antibacterials: Quinolones F. STRUCTURE AND SARs. 39