Lecture 2-Quinolones PDF

Quinolones O Nalidixic acid: (Negram®) 5 4 COOH...

Quinolones O Nalidixic acid: (Negram®) 5 4 COOH 6 3 1-Ethyl-7-methyl-4-oxo-1,4-dihydro- 2 [1,8]naphthyridine-3-carboxylic acid N N 1 8 C2H5  First generation quinolones (lead compound).  Rapidly excreted in urine after oral administration.  Treatment of renal gram -ve infections, (Usually E. Colli). Synthesis: O O C2H5OOC COOC2H5 COOC2H5 COOC2H5 - 2 C2H5OH C2H5I i) NaOH + H3C N NH 2 OC2H5 ii) H+ H3C N N H3C N N H CH 2CH3 Nalidixic acid 1  Disadvantages of nalidixic acid 1) Narrow spectrum [active # gram -ve only) 2) Not suitable for systematic infections 3) Development of bacterial resistance. O Norfloxacin (Noroxin®) F COOH N N HN C2H5 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)qunoline-3- carboxylic acid.  Has broad spectrum # gram –ve & +ve aerobic bacteria  The F atom ►↑ potency # gram +ve organisms & piperazine moiety ↑ antipseudomonal activity.  Uses: UTI & gonorrhea. 2  O O F COOH 8 7 F 9 6 COOH 5 N N N 10 N4 HN N 1O H3C 3 CH3 2 Ciprofloxacin Ofloxacin Uses: Uses:  respiratory infections  Respiratory  Chronic & acute UTI.  UTI.  Gastroenteritis by –ve bacilli.  3S(-)-isomer (levofloxacin) is 8-125  Effective as anti.T.B. times more active than the 3R(+) Both have the same spectrum 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quioline-3-carboxylic acid. 3  O O F COOH F COOH H3C N N N N HN F HN F C2H5 CH3 CH3 Lomefloxacin Sparfloxacin Uses:  has higher potency against gram  Chronic bronchitis +ve & gram –ve bacteria.  Acute cystitis  It has a long elimination half-life of  UTI 18 hr (used once-a-day). 4 MOA super coiled DNA (normally 1000 µm coiled to 1 µm) Inhibition of DNA synthesis, by inhibition bacterial DNA gyrase (topoisomerase II), an enzyme responsible for supercoiling & uncoiling of DNA. SAR 5 SAR Essential. The pyridone ring must be annulated (fused) by aromatic ring, (benzene or O pyridine). 4 3 COOH 6 5 1,4-dihydr 2 R2 7 N N 1 8 Position 2 should be nonsubstituted R1 (substitution reduce or abolish activity). Alkyl substitution at position 1 (R1) by methyl, ethyl and cyclopropyl (small alkyl group) are essential for activity. 6 Substitution at position 6 & 7 modify the spectrum of activity e.g. O Gram- positive organisms F 6 COOH increases the N 7 N antipseudomonal N R2 R1 1. Piperazinyl gp at position 7 increases antipseudomonal activity 2. F atom at position 6 increases the activity # Gram +ve. 7 Classification of quinolones: Two main classifications for quinolones based on 1) Chemical structure or 2) biological properties Chemical classification Bicyclic Tricyclic Nonfluorinated 6-Fluorinated Oxalinic acid Ofloxacin Levofloxacin Nonfluorinated 6-Fluorinated Nalidxic acid Norfloxacin 8 Biological classification: Generations Administration & spectrum Indications 1st generation Nalidixic Acid  Oral with low bioavailability uncomplicated UTI  # gram-ve Not for systemic infections 2nd generation Class I Norfloxacin  Oral with low bioavailability uncomplicated UTI  # gram –ve Not for use in systemic Class II Ofloxacin  Oral and I.V. Complicated UTI Ciprofloxacin  High bioavailability P. aeruginosa (ciprofloxacin only) 3rd generation Levofloxacin  Oral and I.V.  P. aeruginosa, Streptococci. Sparfloxacin  # Gram –ve & +ve 4th generation Trovafloxacin  Oral and I.V.  P. aeruginosa, Streptococci  # Gram –ve, +ve  Staph. Aureus & Anaerobes. 9 Chemical Incompatibilities to quinolones M O O F O N N Metal complex with quinolones N M = Ca, Mg, Al, Fe R1 R2  They chelate heavy metals (Ca2+, Mg2+, Al3+, and Fe2+) → less water- soluble complexes → lose considerable potency.  So, contra-indicated with Ca, Mg, Fe nutrition or with milk 10  Classification of Quinolones GENERAL CLINICAL CLASSIFICATION AGENTS ANTIMICROBIAL SPECTRUM INDICATIONS First Nalidixic acid Gram-negative organisms Uncomplicated generation (NegGram) (but not Pseudomonas species) urinary tract infections Cinoxacin Cinobac) Second Norfloxacin Gram-negative organisms Uncomplicated and generation (Noroxin) (including Pseudomonas species), complicated urinary some gram-positive organisms tract infections and (including Staphylococcus aureus pyelonephritis, Lomefloxacin sexually transmitted (Maxaquin) diseases, prostatitis, skin and soft tissue infections Ofloxacin (Floxin) Ciprofloxacin (Cipro) 11 CLASSIFI ANTIMICROBIAL GENERAL CLINICAL CATION AGENTS SPECTRUM INDICATIONS Third Levofloxacin Same as for second- Acute exacerbations of generation (Levaquin) generation agents plus chronic bronchitis, Sparfloxacin expanded gram-positive community-acquired (Zagam) coverage (penicillin-sensitive pneumonia and penicillin-resistant S. Gatifloxacin (Tequin) pneumoniae) and expanded activity against atypical Moxifloxacin pathogens (Avelox) Fourth Trovafloxacin Same as for third-generation The same as previous generation (Trovan) agents plus broad anaerobic (excluding complicated coverage urinary tract infections and pyelonephritis) plus intra- abdominal infections, pneumonia, pelvic infections 12 Miscellaneous urinary antiinfective agents A) Nitrofurantoin (Macrodantin®) O NH N N O2N O O Nitrofurantoin 1-[(5-Nitrofurfurylidene)amino]hydantoin.  Prophylaxis or treatment of UTI resistant to antibiotics  Inhibits kidney stone growth.  S.E. nausea and vomiting, avoided in part by slowing the rate of absorption of the drug through use of wax-coated large particles (Macrodantin). 13 B- Hexamine (Methenamine, hexamethylene tetramine). 1,3,5,7-Tetraazadmantan. 1 N H+ / H2O 6HCHO + 4NH4 5 N N 3 N 7 Methenamine (Hexamine) MOA  It has no antibacterial activity (prodrug)  In acidic urine hexamine hydrolyzed to → HCHO (active form)  its action was enhanced by lemon juice or vitamin c (they are acidic compounds that increase hydrolysis).  To avoid stomach hydrolysis we use enteric coated tablets or taken before meals. 14 Identification NaOH NH3 odour COOH (CH2)6N4 H 2 HO C O 2H2SO4 OH 6 HCHO HOOC COOH Caramine red colour Derivatives of Hexamine Hexamine Mandelate (Mandelamine) COO H N HC OH N N N  It is water soluble salt  No need for acidifying salts ?? Because Mandelic acid is excreted in the urine increasing its acidity so increase the dissociation of hexamine to HCHO 15 References: 1- Foye's principles of medicinal chemistry. Philadelphia, Lippincott Williams & Wilkins. 2-Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry. Philadelphia, Lippincott-Raven. 16