1,8-Naphthyridines, antibacterial

Several 3-fiuoropyridine derivatives are employed to produce enoxacia, tosufioxacia, and other naphthyridine antibacterials (Table 14). Examples of such iatermediates iaclude 2,6-dichloro-5-fiuoronicotiQonitrile (429), ethyl 2,6-dichloro-5-fiuoronicotiQate (430), 2-chloro-3-fiuoropyridine (393), 6-acetyl-2-(4-acetyl-l-piperaziQyl)-3-fiuoropyridine (431), and 5-fiuoro-2,6-dihydroxynicotiQamide (394). 

Fig. 6.18 Examples of some quinolone/naphthyridine antibacterials illustrating the structural developments over the four generations (1-4) of the drugs...

The 8-position of the quinolone nucleus can often be advantageously substituted by fluorine (58) or chlorine (59) to give compounds with improved antibacterial potency over hydrogen in this position. With 1,8-naphthyridines, activity is reported to be approximately equivalent to the quinolone bearing a hydrogen in this position (60). As an example of this, see the data for norfloxacin (8) and enoxacin (7) in Table 2. 

The antibacterial agent nalidixic acid [389-08-2] (37) is formed by reaction of 2-ainino-6-methylpyridine [1824-81 -3] with an alkoxymethylenemalonic ester to form the 1,8-naphthyridine carboxyUc ester followed by alkylation and ester hydrolysis (37). 

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2-amino-6-methylpyridine (36) proceeds directly to the naphthyri-dine (38) the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. W-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

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... 

Since the discovery, in 1962, by Lesher and co-workers162 that l-ethy]-3-carboxy-7-methyl-l,8-naphthyridin-4-one (nalidixic acid, 154) is a powerful antibacterial agent, numerous publications have... 

A large number of 4-oxo derivatives of the 1,8-naphthyridine ring system have been synthesized and screened for their antibacterial activity. In general, the active compounds are similar to the 1,5-naphthyridine derivative nalidixic acid.114-117... 

As well as their chemical importance, appropriate oxy-1,6-naphthyridines have shown appreciable (but not outstanding) biological activities as metal-binding antibacterials,110 or as antineoplastic agents.572,cf 843 Medorinone, 5-methyl-1,6-naphthyridin-2(lH)-one, has been used as a cardiotonic/vasodilatory agent.490, 716,1224,cf. 320 QXy derivatives of fused/unfused 1,6-naphthyridines have been iso-lated from manne sponges. ... 

The ionization constants,331 NMR spectra,174 and mass spectra1227 of representative amino-1,6-naphthyridines have been compared with those of related amino derivatives. Complexes of l,6-naphthyridin-2-amines with tetracyanoquinodi-methane have been studied.416 4-(3-Dimethylamino-l-methylpropylamino)-l,6-naphthyridine showed significant antimalarial activity.236 X-ray analyses of a number of 5-amino-1,6-naphthyridines have been reported in connection with their antibacterial activities for example, ethyl 5-amino-7-benzylseleno-8-cyano-4-(fur-2-yl)-l,2-dimethyl-l,4-dihydro-l,6-naphthyridine-3-carboxylate (10) proved to be a mixture of two symmetric conformers in each crystal 772 the other related compounds appear to be composed of single conformers.558,560 562 759 781 1289... 

The IR spectra of l,7-naphthyridin-8(7//)-one clearly point to its existence as such rather than as l,7-naphthyridin-8-ol, at least in the solid state and in nonhydroxylic solvents,1035 and (by analogy with related systems) it appears safe to assume that the other isomeric 1,7-naphthyridinones will exist as their keto tautomers. General studies that include the HNMR, UV, and mass spectra1253 of 1, 7-naphthyridinones have appeared. The antibacterial activity of 8-quinolinol, possibly related to its chelation of heavy metals, is evident to a lesser degree in its aza analogs, including l,7-naphthyridin-8(7//)-one." 110 1040 cf76 Other activities are evident.385... 

Since the introduction in 1963 of nalidixic acid (N -ethyl-7-methyl-4-oxo-l,4-dihydro[l,8]-naphthyridinyl-3-carboxylic acid) as a systemic Gram-negative antibacterial agent, many related derivatives have been synthesized. These types of compounds have received much attention and interest by virtue of their chemical and clinical properties. The methods reported in the chemical literature for preparing C-6- and C-3-substituted 4-oxo[1.8]naphthyridines are somewhat limited. These methods involve the condensation of substituted 2-aminopyridines with suitable 3-ethoxyacrylates, followed by cyclization. Recently, such substituted 4-oxo-l,4-dihydro[1.8]naphthyridines have been obtained using the Suzuki reaction (Eq. (38)) [69]. 

These heterocycles are prepared exclusively by the electrocyclization of in situ generated ortho-diazonium thiolates <78PJC2039>. This is illustrated by the syntheses of (i) antiinflammatory 7-amino[l,2,3]thiadiazolo[5,4-6]pyridine-6-carboxylic acids (202) <76USP3965108> from penta-substituted pyridines (201) and (ii) antibacterial thiadiazolo[5,4-h][l,8]naphthyridine carboxylic acids (203) (Equation (25)) <80CPB76l>. 

Medicinally important naphthyridine derivatives such as analogues of the antibacterial agent naladixic acid (445) <91MI 715-02) have been discussed in CHEC-I <84CHEC-i(2)58i> and in another review <83AHC147>. Tosufloxacin tosylate (446) is an example of a nalidixic acid analogue. 

Hong CY, et al. Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines synthesis and antibacterial activity of 7-(4-(aminomethyl)-3-(methoxyimino)-pyrrolidin-l-yl)-l-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[l,8]naphthyridine-3-car-boxylic acid (LB 20 304). J. Med. Chem., 1997, 40, 3584-3593. 

Some of the 7-alkylamino- and arylamino-substituted derivatives of l-ethyl-l,4-dihydro-6-nitro-4-oxo-l,8-naphthyridine-3-ethylcarboxylate showed nearly the same antibacterial activity as metronidazole against Trichomonas vaginalis (77MI2 79YZ155). 

Enoxadn, USP. l-Ethyl-6-fluoro-l.4-dihydro-4-oxo-7-(I-piperazinyI)-I,8-naphthyridine-3-carboxylic acid (Pene-irex) is a quinolone with broad-spectrum antibacterial activity that is used primarily for the treaimenl of urinary tract infections and. sexually transmitted diseases. Enoxacin has been approved for the treatment of uncomplicated gonococcal urethritis and has also been shown to be effective in chancroid caused by Haemophilus ducreyi. A single 400-mg dose is used for these indications. Enoxacin is also approved for the treatment of acute (uncomplicated) and chronic (complicated) urinary tract infections. 

With the aim of studying their structure-antibacterial activity relationships, a series of new 7-substituted 6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acids... 

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