Quinolones, structure

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

A substituted quinolone structure is common to the group of quinolone antimicrobials, many of which are also fluorinated. There is sufficient similarity of structure as well as molecular shape to suggest that, with the appropriate antigen, a generic... 

A 1,3-dipolar cycloaddition using oxime derivatives yielded the tetrahydroquinoline derivative 25 (Equation 58) <2005S3423>. It was advantageous that the product precipitated out of the aqueous reaction medium in excellent yield. Carbenoid-insertion reactions have been demonstrated to produce the ring-extended quinolone structure 26 from simple substituted anilines (Equation 59) <2003TL7433>. The C-H insertion onto the aromatic ring can vary. 

The evolution of the quinolones, which began with nalidixic acid and has produced the modem fluoroquinones moxifloxacin, gatifloxacin and gemifloxacin, was based not only on modifications of the basic quinolone structure but also on the development of new cyclic amines for the 7-position. The cyclopropyl radical, which was introduced for the first time in ciprofloxacin, remains the most effective substituent for the 1-position. Moxifloxacin is an 8-methoxy fluoroquinolone with a novel enantiomerically pure S,S-2,8-diazabicyclo[4.3.0]non-8-yl radical in the 7-position. 

Apparently, the above results were quite contrary to those observed in the photocyclization of 7V-benzoylenamines described in Section Il,A,l,a. N-Acylanilides carrying an electron-withdrawing group in the ortho position underwent smooth photocyclization exclusively to the root of the substituent that was then migrated in a 1,5 manner suprafacially to afford the lactam (5), having the substituent in the 3 position of the quinolone structure. 

Allyloxy-2,3-dimethylquinoline on heating without a solvent at 200° for only 30 minutes afforded in yields as high as 92% a product with a quinolone structure. Confirmation of this formulation came from the following series of transformations (1) treatment with phosphorus oxychloride which gave the 4-chloro compound and... 

Several further species of Flindersia have been examined for alkaloids and other extractives and the chemistry of this genus has been reviewed (118). The only new alkaloid found was iflflaiamine ([a] n — 0.6° hydrate, mp 62°-63° picrate, mp 207°-209°), the sole alkaloid of the wood of Flindersia ifflaiana F. Muell. (119), which is a dihydrofuroquinoline (XX). Its structure was largely elucidated by spectroscopic measurements. Its UV- and IR-spectra showed it to be a 2-alkoxy-4-quinolone, and the NMR-spectrum showed the presence of three C-methyl groups and one A-methyl (attached to aromatic ring N), a 1,2-disubstituted benzene ring, and other evidence supporting the 2-alkoxy-4-quinolone structure. 

On alkaline hydrolysis the alkaloid gave a phenolic compound (XXI), whose NMR-spectrum indicated a 4-hydroxy-2-quinolone structure and which gave an iodoform reaction. Attempts to synthesize iflflaiamine have not succeeded so far. 

The uniqueness and importance of the F substituent at the 6 position of the 4-quinolone structure was exemplified showing that a series of quinolones carrying the piperazinyl function at that position, along with the F at C-8 (structure C), were devoid of activity against S. aureus, E. coli, and P. aeroginosa. The reason for this surprising effect from simply switching substituents is not apparent. 

In general, these properties of hydroxy substituted derivatives will be present in pi-deficient nitrogen heterocycles with benzo fusion or with multinitrogen substitution. For example, the 4-OH group on quinoline tautomerizes to the 4-quinolone structure (Scheme 6.36). 

Tillotson GS. 1996. Quinolones Structure-activity relationships and future predictions. Journal of Medical Microbiology 44(5) 320-324. 

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. ... 

---