Quinolones stability

Degani et al., 1968). A comparison of the basicity of these compounds with those of the corresponding pyridone analogues (2- and 4-quinolones and 9-acridones) is given in Table 4. The order of basicities for these compounds is NH > S > Se > O. They are all protonated on the carbonyl oxygen. Such is the resonance stabilization of the pyrone cations that they do not accept any further... 

Polar solvents stabilize polar tautomers. In the vapor phase at equilibrium both 2- and 4-hydroxypyridines exist as the pyridine rather than as the pyridone. 3-Hydroxypyridine, which in water is an approximate 1 1 mixture of OH and NH forms, also exists as the OH form in the vapor phase. However, even in the vapor phase, Z- and 4-quinolones remain predominantly in the NH (oxo) forms. Hydrocarbons or other solvents of very low polarity might be expected to give results similar to those in the vapor phase, but intermolecular association by hydrogen bonding often leads to a considerably greater proportion of polar oxo tautomers. 

Takacs-Novak et al. (14) used a potentiometric assay in combination with UV spectroscopy and NMR to study the acid-base properties and protonation equilibria for lomefloxacin and other quinolone antibacterials. Okabayashi et al. used potentiometric measurements to determine the stability constants of metal ions with several quinolones including lomefloxacin (20). 

Several groups have adapted the method to analyze residues in a variety of matrices. Acetic acid (HQAc, 1%) and sodium acetate have been widely used to adjust and maintain pH and promote stability and recovery of base-sensitive residues. HOAc was used to adjust pH by Stubbings and Bigwood to determine residues [sulfonamides, quinolones, (fluoro)quinolones, ionophores, and nitroimidazoles] in chicken muscle. Buffering to acidic conditions improved the extraction efficiency of quinolones. Aeetonitrile extracts were subsequently purified by dSPE (see also Section 4.4.6.1) over Bondesil NH2 sorbent. An aliquot of the extracts was evaporated to dryness and re-dissolved in acetonitrile water (90 10, v/v) before LC-MS/MS analysis. Validation was performed on chicken muscle samples, and matrix-matched standards were used because suppression of the MS response was observed for many of the target analytes. 

It is believed that eertain of the quinolone functional groups (3-carboxyl and 4-oxo) form insoluble chelates with aluminium and magnesium ions within the gut, which reduces their absorption. " The stability of the chelate formed seems to be an important factor in determining the degree of interaction. It has been suggested from animal studies that adsorption of quinolones by aluminium hydroxide re-precipitated in the small intestine may be a factor in the reduced bioavailability of quinolones. See also Quinolones + Iron or Zinc compounds , p.336. 

Unfortunately, Vertex s initial foray into varying the quinolinone moiety on 2 (ECso = 2.1 aM) came empty-handed. Replacing the quinolinone with quinolone, pyridine, alkylation of the NH on quinolone 2, and replacing the quinolinone moiety with pyridopyrimidine core structure all yielded analogs with inferior potentiator activities. Meanwhile, the naphthanol derivative 3 retained the potentiator activity (ECso = 3.5 jM). The lesson learnt from this SAR exercise is that the two features are essential to the potentiator activity (i). The hydrophobic phenyl ring is needed, and (ii). The quinolinol tautomer 2 (which is more stabilized via hydrogen bond) is favored. 

Here a ground state pyridone and quinolone structure is present in the parent ligand as well as being an important resonance form in many metal complexes. It has also been shown possible to stabilize the 1,3-cyclohexadienone form by attachment to a triosmium cluster framework. ... 

On the other hand, in the TS8 the fluorine atom must move away from this proton, and the whole number of the stabilizing noncovalent C-H... F interactions is reduced to five. One of these interactions is with the ortho-proton of the quinolone substituent that explains its axial orientation. 

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