Quinolone, analogues

Perhaps the only contribution of much chemical interest in the Cinchona group during the year concerns the biotransformation of quinidine (234) in man, and the partial synthesis of one of the metabolites. The two metabolites identified were 3-hydroxyquinidine (235) and 2 -quinidinone, the 2-quinolone analogue of quinidine the former of these was prepared from quinidine by degradation to the ketone (236) (not previously prepared), and re-introduction of the vinyl group by a Grignard synthesis (Scheme 32). 

Pyridone and 2-quinolone analogues are well known biologically active heterocyclic scaffolds. In 2004 Kappe and coworkers generated libraries of 3,5,6-substituted 2-pyridone derivatives by rapid microwave-assisted solution-phase methods using a one-pot, two-step procedure [61]. This three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal (DMFDMA), and methylene-active nitriles led to 2-pyridones and fused analogues in moderate to good yields (Scheme 10.26). 

Kurasawa Y, Matsuzaki 1, Satoh W, Okamoto Y, Kim HS (2002) Quinolone analogues 4. Synthesis of l-methyl-3-trifluoromethylpyridazino[3,4-h]quinoxalin-4(l//)-ones. Heterocycles 56 291-304... 

Pyridyl-4-bromo-6-oxo-5,6,7,8-tetrahydrothiazolo[5,4-g]quinolones and analogues were prepared and tested as potential inotropic agents for treatment of heart failure. For example, the 2-(4-pyridyl) substituted thiazoloquinolone 38 gave a 122% increase in contractility of guinea pig papillary muscle (89EUP1). 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

Although the thermal cyclization step in the Gould-Jacobs method proceeds with good yield for simple quinolones, the yields in multisubstituted analogues are low and unsatisfactory. In order to bypass the thermal cyclization step, a second method was introduced in the late 1980s and early 1990s via o-halobenzoic acid derivatives. This method, which is now the most pop-... 

According to molecular modeling studies, at the ground state the 6-lluoro analogue of 81 overlaps perfectly with the structure of norfloxacin (a well-established quinolone antibacterial agent) and is predicted to exhibit promising antibacterial activity. 

In 1984, the results of a study investigating amino-substituted alicyclic amino groups as replacements for the 7-piperazinyl group, common to many of the most potent quinolones, was reported [73], This comprehensive study systematically examined variations at the 7-position of the 1,8-naphthyridine nucleus. The in vitro antibacterial activities for several of these enoxacin analogues (19) are summarized in Table 6.6. The most noteworthy feature of these data is that replacement of the piperazin-l-yl group with a 3-aminopyr-rolidin-l-yl moiety (compound (19b)) results in an enhancement in potency... 

Quinolones possessing a 7-(3-aminopyrrolidin-l-yl) substituent are particularly potent antibacterial agents. However, they often have very low solubility. Based on the observations that the hydroxymethylpyrrolidine (38) is significantly more potent against bacteria than its enantiomer (39) (the hydroxymethyl substituent in (39) apparently has a deleterious effect on activity while the same substituent in (38) has little effect on potency based on comparisons with the unsubstituted pyrrolidine analogue (40)) [84] and the enantiomer (41) is at least as potent as,... 

In another study concerning the conformational requirements of I-cyclopropyl-quinolones and their relationship to DNA gyrase inhibition, the conformation-ally constrained cyclopropane derivative (62), related to ofloxacin was prepared and evaluated in whole cells and for inhibition of DNA gyrase [95] the gem-dimethyl analogue (35), discussed earlier in the context of QSAR studies... 

A series of 7-diazabicycloalkyl quinolones has been prepared and found to exhibit excellent broad spectrum activity against important veterinary pathogenic bacteria [105], The structures of several of these interesting bicyclic analogues (76) as well as MIC data are summarized in Table 6.28. Compound (76e) (danofloxacin), which also exhibits excellent p.o. and s.c. activity in a mouse protection model for Pasteurella multocida [ 106], is undergoing development for use in veterinary medicine. It has been shown to exhibit excellent bioavailability properties in cattle, swine and poultry [107] and is efficacious in models for the treatment of respiratory diseases in food-producing animals [108],... 

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... 

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