quinolone

Quinolone antibacterial : 

Quinolone antibacterial Development, mode of action, structural features, SAR, synthetic approaches and screening method of fluoroquiolones & oxazolidinones, anti-TB

A timeline for antibiotic research. : 

A timeline for antibiotic research.

Origin of the quinolones : 

Origin of the quinolones Gram negative Escherichia coli Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis [1962]

Mechanism of action : 

Quinolones inhibit the action of bacterial DNA gyrase enzyme. This enzyme is responsible to supercoil and compact bacterial DNA molecules into the bacterial cell during replication. This action is accomplished by modifying the topology of DNA via, supercoiling and twisting of these macromolecules to permit DNA replication or transcription. Mechanism of action

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Gram - ve Gram + ve

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Classification : 

1st generation: Cinoxacin, flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidic acid. 2nd generation: Ciprofloxacin, enoxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin. 3rd generation: Balofloxacin, grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin. Classification

Classification : 

4th generation: Clinafloxacin, gemifloxacin, moxifloxacin, gatifloxacin, sitafloxacin, trovafloxacin. In development: Ecinofloxacin, prulifloxacin. Veterinary use: Danofloxacin, difloxacin, enrofloxacin, marbofloxacin, orbifloxacin, sarafloxacin. Classification

Uses : 

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

Adverse effects : 

Photosensitivity reactions - Nature of the 8-position substituent Convulsions particularly concurrent administration of NSAID Fenbufen- Nature of the 8-position substituent Arthralgia and joint swelling - in children Adverse effects

Fluoroquinolone binding : 

Fluoroquinolone binding

Quinolone binding mode to DNA gyrase : 

Quinolone binding mode to DNA gyrase

SAR of quinolones : 

SAR of quinolones 1. Substituent at N-1 position: A compilation of active N-1 quinolone substituent's is shown below with an emphasis on overall in vitro potency.

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Activity against anaerobes is generally lacking in this group.

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Enhanced Gram –ve, and good anaerobic

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Good anaerobic, toxic N-tert-butyl analogues were found to be unexpectedly potent in vitro, especially against Gram positives. But is not very stable in acidic solutions Tosu: thrombocytopenia and nephritis, and hepatotoxicity Tema: allergic reactions and hemolytic anemia Jan-June 1992 [abbott], Sara 2001 Trova: hepatotoxicity, Nigeria 1996 [Pfizer]

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the potency of N-1 analogues against Gram-positives follows the order aryl > ethyl > 1,8-fused > c-propyl Against Gram-negatives the order is slightly different: Ethyl, c-propyl > aryl

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2) The simple replacement of C-2 hydrogen has generally to be disadvantageous. Eg: C-2 methyl or hydroxyl/SH groups. However, some derivatives containing a suitable C-1, C-2 ring have been shown to possess notable activity. 3) Without doubt, the C-3 carboxylic acid moiety is most commonly encountered. Other acidic groups such as sulfonic acid, phosphonic acid, tetrazole, as well as derivatisation as an ester results in a loss of antibacterial activity, The carboxyl group at C-3 needs to be coplanar with the C-4 carbonyl so that it can effectively hydrogen bond with DNA

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4) The C-4-oxo group of the quinolone nucleus appears to be essential for antibacterial activity. Replacement with 4-thioxo or sulfonyl group leads to a loss of activity, N-1 alkyl & 4-C=O C-4a Substituted Analogues: 5) The incorporation of an amino group at the C-5 position has proven beneficial in terms of antibacterial activity. The order of activity at R5: NH2, CH3 > F, H > OH, OR, SH, SR [small & polar].

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6) The incorporation of a Fluorine atom at the C-6 position of the quinolone is monumental. The order of activity at R6: F > Cl, Br, CH3 > CN. Substituents at C-6 in the early investigations were generally limited to the terminus of a methylenedioxy bridge to C-7 (oxolinic acid, miloxacin, and cinoxacin), CH (nalidixic acid and rosoxacin), and N (pipemidic acid and piromidic acid). C-6 fluorine substituent conveys enhanced DNA gyrase potency and enhances cell penetration. C-6 F may play a role in the potential mammalian genotoxicity [C. Bond with DNA] and central nervous system side effects of quinolones. C-H, C-NO2

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7) The introduction of a piperazine moiety at C-7 was a landmark development. Other aminopyrrolidines also are compatible for activity, The nature of the C-7 substituent (along with C-8) also strongly affects the target preferences (DNA gyrase and/or DNA topoisomerase IV) of quinolones. The piperazinyl analogues usually have enhanced potency against Gram negatives, whereas the pyrrolidinyl analogues have enhanced activity against Gram-positives. Aromatic leads to human

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8) A hydrogen atom at the C-8 or a nitrogen atom (a naphthyridone) is the most common. In general, a C-8 fluoro substituent offers good potency against gram negative pathogens [phototoxic, improves oral absorption], while a C-8 methoxy moiety is active against gram positive bacteria. The order of activity at R8: F, Cl, -OCH3 > H, CF3 > methyl, vinyl, propargyl. C-8 substituents have an important effect on in vivo efficacy and the antimicrobial spectrum of quinolones. A halogen (F or Cl) at the 8- position improves oral absorption.

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9) The joining of N-1group to the C-8 position with oxazine ring leads to active Ofloxacin. Rigidification of the N-1 substituent in this way resulted in a significant enhancement in anti Gram-positive activity although some anti Gram negative activity was concomitantly lost. Resolution of ofloxacin leads to a doubling of potency O, S, CH- No change in activity

Structure-Toxicity Relationships : 

Temafloxacin was withdraw-severe hemolytic reactions, Trovafloxacin-hepatotoxicity Grepafloxacin-cardiotoxicity Structure-Toxicity Relationships

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1 2 3 4a-c 5a-c 6a-c 7-9a-q

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1 2 3 4 5 8a-n 9a-n 10k,m

Biological Screening : 

Biological Screening In-vitro: Agar dilution In-vivo: Mouse protection test LD50, Infection, Treatment, 1 Week. Phototoxicity evaluation 3 groups-drug, lome, vehicle. UV light irradiation of ca. 18 J/cm2. 4hour. Before dosing, at the end of the irradiation period and at ca. 24, 48, 72 and 96 h after dosing, both ears of each mouse were evaluated for changes indicative of a positive response, namely erythema, oedema or a measurable increase in ear thickness.

Schematic representation of interactions between ATP and GyrB : 

Schematic representation of interactions between ATP and GyrB

Schematic diagram of interactions between novobiocin and GyrB : 

Schematic diagram of interactions between novobiocin and GyrB Vertex Pharmaceuticals

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Compound 1 was identified in a high-throughput assay targeting the Gyr B subunit. Approximately 30 000 compounds pre-filtered for drug like properties. The benzimidazole carbamate, 1, was identified as a micromolar GyrB inhibitor with MIC values greater than 16 μg/mL against all organisms. Compound 15 E. coli gyrase <0.004 μM E. coli topo IV 0.023. Minimum inhibitory concentration (μg/mL) S. pneumonia 0.004, S. aureus 0.031. J. Med. Chem. 2008, 51, 5243–5263

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GyrB IC50 (µM) 0.054 Bioorganic & Medicinal Chemistry Letters 19 (2009) 894–899

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enzyme potency (IC50 = 0.2 µM) and (MIC’s = 0.015–0.06 l g/mL). Bioorg. Med. Chem. Lett. 17 (2007) 1312–1320

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IC50 (µg/mL) Gyrase 0.5; S. aureus 4; E. faecalis 8Bioorganic& Medicinal Chemistry Letters 14 (2004) 2863–2866