Finafloxacin
[(-)-8-Cyano-1-cyclopropyl-6-fluoro-7-((4aS,7aS)-hexahydropyrrolo(3,4-b)-1,4-oxazin-6(2H)-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid] is an active member of specially designed pH-activated 8-cyanofluoroquinolones;
developed to treat serious bacterial infections associated with an acidic
environment, including urinary tract infections (UTIs) and Helicobacter pylori
infections. The compound exhibits optimal efficacy in slightly acidic
environments (pH 5.0-6.0), under which other fluoroquinolones lose activity [1].
Finafloxacin is highly selective for bacterial type II topoisomerases, including DNA gyrase and DNA topoisomerase IV. In December 2014, a topical otic suspension formulation of Finafloxacin, was approved in the USA for the treatment of acute otitis externa (in individuals aged greater than 1 year) caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus.
Acute Otitis Externa: a common condition
involving inflammation of the ear canal. The acute form is caused primarily by
bacterial infection, with Pseudomonas
aeruginosa and Staphylococcus aureus
the most common pathogens.
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| Finafloxacin: 2D and 3D Structure |
Fluoroquinolones: What, why and how?
Helicobacter pyroli (H. pyroli) is a microaerophilic
Gram-negative bacterium that lives on the lining of the stomach and infects 50%
of the human population worldwide. Moreover, H. pyroli is only bacterium designated as a Class I carcinogen by
International Agency for Research in Cancer.
Infection
of the bacterium causes chronic superficial gastritis, chronic gastritis,
gastric ulcers and also gastric cancer in humans.
The
fluoroquinolones (FQs) such as Ciprofloxacin and Norfloxacin are modified quinolone
antibiotics which are widely used for the treatment of various bacterial
infections. Most antimicrobials are effective against H. pyroli in vitro, but
in vivo at lower pH environment of the gastric mucosa the activity reduces
dramatically for most of the drugs.
The
mode of action of the FQs antibiotics involves inhibition of two bacterial
enzymes: DNA gyrase and topoisomerase IV enzymes. DNA gyrase (topoisomerase II)
is an essential enzyme involved in the replication, transcription, and
reparation of the bacterial DNA and topoisomerase IV is an enzyme responsible
for the separation of daughter DNA strands during bacterial cell division. In
Gram-negative organisms DNA gyrase is the primary target, in the case of
topoisomerase IV the Gram-positive bacteria are the most affected ones [2].
Finafloxacin Synthesis
Tet Lett 2009, 50, 2525-2528:
Intermediate 1: The article reports a convenient method to prepare the chiral pure desired bicyclic amine using commercially available less expensive (R)-1-phenyl-ethanamine. The diastereomers were purified by using crystallization technique.
Intermediate 2: Synthesis of 7-chloro-8-cyano-1-cyclopropyl-6-fluoroquinolone
Final Synthesis:
US6133260A: This the one of the oldest reported synthetic procedure for preparing gram yields of Finafloxacin. It appears to be the favoured one for an industrial process.
Identifications:
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| 1H NMR (Estimated) for Finafloxacin |
Experimental: 1H NMR
(400 MHz, DMSO-d6, δ
ppm) 1.06-1.08 (m, 1H), 1.19-1.24 (m, 2H), 1.410-1.42 (m, 1H), 2.99-3.03 (m,
1H), 3.08-3.15 (m, 2H), 3.73-3.95 (m, 7H), 3.97-4.11(m, 1H), 4.12-4.14 (m, 1H),
7.92 (d, 1H, J = 14.4 Hz), 8.7 (s, 1H).
Sideeffects: Finafloxacin (IV and oral) was well tolerated
with low rates of mainly gastrointestinal adverse events. The sideeffects of Finafloxacin
can be visualized in its pharmacologically active state, such as:
Topical: The most common adverse effects (AEs)
were ear pruritus and nausea, both of which occurred in 1 % of patients.
Oral (150-800 mg daily): Adverse events (AEs)
associated with Finafloxacin included diarrhoea, nausea, headache and
nasopharyngitis. There were no clinically relevant changes in laboratory or
cardiovascular parameters.
IV Finafloxacin single doses (200-1000 mg) or
multiple doses (600-1000 mg): Adverse events reported by 60% of patients’
were musculoskeletal disorders), headache, diarrhoea and administration site
disorders. There were no reports of serious adverse events.
References:
1. Stubbings, W.; et. al. In Vitro Spectrum of Activity of Finafloxacin, a Novel, pH-Activated Fluoroquinolone, under Standard and Acidic Conditions. Antimicrob Agents Chemother 2011, 55(9), 4394-4397. (free article)
2. Hong, J.; et. al. A novel approach to Finafloxacin hydrochloride (BAY35-3377). Tet Lett 2009, 50(21), 2525-2528. (FMO only)
3. Matzke, M.; et. al. Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. US6133260A
