Garenoxacin Chemical Properties

Melting point:

226-227°; mp 234-235°

alpha 

D27 -9.0° (c = 0.10 in N,N-dimethylformamide)

Boiling point:

581.5±50.0 °C(Predicted)

Density 

1.421±0.06 g/cm3(Predicted)

storage temp. 

Hygroscopic, -20°C Freezer, Under inert atmosphere

solubility 

DMF (Slightly, Heated), DMSO (Slightly, Heated), Methanol (Slightly, Heated)

form 

Solid

pka

6.44±0.50(Predicted)

color 

Off-White to Pale Yellow

Stability:

Hygroscopic

InChI

InChI=1S/C23H20F2N2O4/c1-11-15-5-2-12(8-13(15)9-26-11)16-6-7-17-19(21(16)31-23(24)25)27(14-3-4-14)10-18(20(17)28)22(29)30/h2,5-8,10-11,14,23,26H,3-4,9H2,1H3,(H,29,30)/t11-/m1/s1

InChIKey

NJDRXTDGYFKORP-LLVKDONJSA-N

SMILES

N1(C2CC2)C2=C(C=CC(C3C=CC4=C(C=3)CN[C@@H]4C)=C2OC(F)F)C(=O)C(C(O)=O)=C1

Garenoxacin Usage And Synthesis

Description

Garenoxacin is a new quinolone antimicrobial agent that exhibits a broad spectrum of activity against both Gram-negative and Gram-positive organisms, including the important community-acquired respiratory pathogens S.pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In addition, it has potent activity against several resistant strains such as multidrug-resistant S.pneumoniae, methicillin-resistant S.aureus (MRSA), and vancomycin-resistant enterococci (VRE). It was launched in Japan as an oral treatment for respiratory tract and otorhinolaryngological infections. As with other quinolone antibiotics marketed in recent years, the mechanism of action of garenoxacin involves dual inhibition of two essential bacterial enzymes, DNA gyrase and topoisomerase IV. The lack of 6-fluoro substituent does not adversely affect its potency of inhibiting DNA gyrase (Escherichia coli, IC50 0.17 mg/mL) or topoisomerase IV (S. aureus, IC50 2.19 mg/ mL).
In human pharmacokinetic studies, oral garenoxacin results in dose-proportionate increases of plasma Cmax and AUC values at doses ranging from 50 to 1,200 mg. Its oral bioavailability is about 95%, and the mean terminal half-life is 15.4 h.
The most common adverse events associated with garenoxacin were rash, dizziness, nausea, headache, and pruritus. Garenoxacin is chemically derived in a sequence of 14 steps, 12 of which entail the construction of a key quinolone intermediate, 7-bromo-1- cyclopropyl-8-(difluoromethoxy)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. Subsequently, Suzuki cross-coupling reaction of this intermediate with (R)-[1-methyl-2-(trityl)isoindolin-5-yl]boronic acid, followed by deprotection of the trityl group and ester hydrolysis with hydrochloric acid gives garenoxacin. The chiral isoindoline reagent is obtained from racemic 5-bromo-2-methylisoindoline via coupling with N-CBZ-L-phenylalanine, separation of diastereomers by chromatography, cleavage of the chiral auxiliary, N-tritylation, halogen-metal exchange with butyllithium, and boronation with triisopropyl borate.

Originator

Toyama (Japan)

Uses

Des-F(6)-quinolone antibacterial; topoisomerase II inhibitor. Antibacterial.

Definition

ChEBI: A quinolinemonocarboxylic acid that is 1,4-dihydroquinoline-3-carboxylic acid that is substituted by a cyclopropyl group at position 1, an oxo group at position 4, a (1R)-1-methyl-2,3-dihydro-1H-isoindol-5-yl group at po ition 7, and a difluoromethoxy group at position 8.

brand name

Geninax

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