Quinolone, 4-methoxy

The relatively low development of resistance is also reflected in the low MPC [245], which defines the threshold concentration of anti-infectives sufficient for preventing the development of resistant populations. For clinical use, the MPC must be below the serum concentration or the concentration in the infected tissue. This requirement is met by the 8-methoxy quinolones moxifloxacin and gati-floxacin [246]. Tests carried out on l-cyclopropyl-7-piperazinyl-quinolones showed... 

Hosaka M, et al. In vitro and in vivo antibacterial activities of AM-1155, a new 6-fluoro-8-methoxy-quinolone. Antimicrob. Agents Chemother., 1992, 36, 2108-2117. 

MacGowan AP, et al. Bay 12-8039, a new 8-methoxy-quinolone comparative in-vitro activity with nine other antimicrobials against anaerobic bacteria. 

MacGowan A. Moxifloxacin (Bay 12-8039) a new methoxy quinolone antibacterial. Expert Opin. Invest. Drugs,... 

In vivo activity of BAY12-8039, a new 8-methoxy-quinolone, in a mouse model of tuberculosis. In 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract E-210,1998. 

Stass H, et al. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob. Agents Chemother., 1998, 42, 2060-2065. 

Recently kinetic data have become available for the nitration in sulphuric acid of some of these hydroxy compounds (table 10.3). For 4-hydroxyquinoline and 4-methoxyquinoline the results verify the early conclusions regarding the nature of the substrate being nitrated in sulphuric acid. Plots of log Q against — (Lf + logioflHao) fo " these compounds and for i-methyl-4-quinolone have slopes of i-o, i-o and 0-97 at 25 C respectively, in accord with nitration via the majority species ( 8.2) which is in each case the corresponding cation of the type (iv). At a given acidity the similarity of the observed second-order rate constants for the nitrations of the quinolones and 4-methoxy-quinoline at 25 °C supports the view that similarly constructed cations are involved. Application of the encounter criterion eliminates the possibilities of a... 

Brassard " applied the Conrad-Limpach reaction as an approach to the A-B ring system of Phomazarin. While the overall yield was only 23%, he showed that a methoxy group was an acceptable substituent on enamino-ester 46 and for the subsequent cyclization to quinolone 47. 

The aposematic beetle, Metriorrhynchus rhipidius, contains three pyrazines as warning odor components and two amides as bitter principles (Tables III, V, and VIII) (97). Of the three components with the beetlelike odor, the most characteristic is 2-methoxy-3-isopropylpyrazine (24b). The other two components are 2-methoxy-3-methylpyrazine (24a) and 2-methoxy-3-sec-butylpyrazine (24d). It would seem likely that these compounds will occur in the defensive systems of the aposematic beetles. The two amide components, detectable in the hemo-lymph exuded by adult beetles, are 3-phenylpropanamide (130) and l-methyl-2-quinolone (57), the latter being the major component. It seems likely that these bitter principles contribute to distastefulness to potential predators. 

Another structurally related series is the 2-ary 1-1,8-naphthyridin-4-ones (37 to 48, see Table 6.7), which contain a second nitrogen in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or a-naphthyl groups at the C-2 position showed potent cytotoxicity in the NCI 60 human tumor cell line panel with GI50 values in the low micromolar to nanomolar range (Tables 6.7 and 6.8).51 The tumor cell line selectivity varies with the various substituents. 2-(3 -Methoxyphenyl)-naphthyridinone (37) was significantly more cytotoxic in several cancer cell lines than the corresponding 2-(3 -meth-oxyphenyl)-quinolone (36). Both compound classes were potent inhibitors of tubulin polymerization the 2-ary 1-1,8-naphthyridin-4-ones had activity nearly comparable with those... 

Oxidation of the triethyl derivative with KMn04 yielded the known iso-quinolone 4 and the diacid 9, which was converted to 10 with CH2N2. Irradiation of the singlet aromatic protons adjacent to the methoxys in 4 and 10 showed... 

The wood of this plant yielded, among other and neutral products, 4-methoxy-l-methyl-2-quinolone (mp 99-103°). The bark yielded nitidine, aricine, chelerythrine, isolated as derivatives, and oxynitidine (mp 283-285°). In addition l-( + )-armepavine metho salt was also found (171). 

Haplopine (1 R1 = H, R2 = OH, R3 = OMe) 4-Methoxy- l-methyl-2-quinolone Robustine Skimmianine... 

Non-hemiterpenoid Quinolines.—New sources of the simple quinolines 4-methoxy-l-methyl-2-quinolone and its 8-methoxy-derivative (folimine) have been reported the former was isolated from Myrtopsis sellingii9 and from Zanthoxylum cuspidatum,16 and folimine was shown to be a constituent of Haplophyllum perforatum.5 The latter species also contains foliosidine (9), previously isolated from H. foliosum. The micro-organism Pseudomonas aertiginosa has been shown to contain 2-(hept-l-enyl)-4-quinolone (12).10 The structure of the alkaloid was established by n.m.r. and mass spectroscopy and by its synthesis from aniline and the j3-keto-ester Me(CH2)4CH=CHC0CH2C02Me. 

Japonine (16), the 3-methoxy-4-quinolone of Orixa japonica (see Vol. 2), has beeen synthesized21 (Scheme 2). The key compound (15 R = OMe) was prepared in good yield by the method used to make the analogous 3-hydroxy-4-quinolone (15 R = H) methylation with methyl iodide and potassium hydroxide in DMF then afforded japonine as the major product. 

The phototoxicity displayed particularly by the 8-halogenoquinolones (fleroxacin, sparfloxacin, lomefloxadn, dinafloxacin and BAY Y 3118) [263] plays virtually no role in the 8-methoxy-substituted quinolones moxifloxacin [237,256,264] and gatifloxadn. 

New quinolones which contain a substituted pyrrolidinyl substituent as the amine radical in the 7-position are also currently being developed for use in veterinary medicine. These include pradofloxacin 91 with an S,S-2,8-diazabicy-clo[4.3.0]non-8-yl radical in the 7-position and a novel 8-cyano group [284,285], and premafloxacin 92 with a 3-(l-methylaminoethyl)-l-pyrrolidinyl radical in the 7-position and an 8-methoxy group [286,287]. 

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. 

Lu T, Zhao X, Drlica K. Gatifloxacin activity against quinolone-resistant gyr-ase allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy group. Antimicrob. Agents Chemother., 1999, 43, 2969-2974. 

For the preparation of 4-(1.2.3.4-tetrahydroquinolino)-phenol 17 three different procedures were worked out [Eqs. (6)-(8)]. 17 was prepared by reacting N-p-methoxyphenyl-anthranilic acid with acetic anhydride and subsequent saponification to l-p-methoxyphenyl-4-hydroxy-2-quinolone, reaction withPOCl3 to form l-p-methoxyphenyl-4-chloro-2-quinolone, hydrogenation to l-(p-methoxy-phenyl)-3.4-dihydro-2-quinolone, splitting the ether with HBr to l-(p-hydroxy-phenyl)3.4-dihydro-2-quinolone, and reduction with LiAlH4 [Eq. (6)J. Another synthetic possibility was the reaction of p-anilinophenol with (3-propiolactone and subsequent cyclization to l-(p-acetoxyphenyl)2.3-dihydro-4-quinolone 18. The next step, the Wolff-Kishner reduction, led directly to the desired product [Eq. (7)]. The third way, the direct amination of p-iodoanisole with 1.2.3.4-tetrahydro-quinoline and the subsequent splitting of 4-(1.2.3.4-tetrahydro-quinolino)-anisol with HBr was the best one [Eq. (8)]. Saponification of l-(p-acetoxyphenyl>2.3-... 

The chemical structure at position 8 in the quinolone ring probably determines the phototoxic potential, since the introduction of a methoxy group at this position markedly reduces the phototoxicity of individual drugs (65). 

A somewhat more complex 4-methoxy-2-quinolone is the alkaloid foliosidine (VIII) (inp 141°-142°) from Haplophyllum foliosum Vved. (see Section VI). The 2,3-dihydroxyisopentyloxy side chain, also found in evoxine and maculosine, was shown to be present by periodic acid oxidation to acetone and an optically inactive aldehyde. 

Methoxy-l-methyl-2-phenyl-4-quinolone (XXVIII) C17H15NO2 198-200 0 12... 

The UV-spectrum of lunacridine, which is unchanged in acid or alkali, is consistent with the presence of a 2-quinolone system the batho-chromic shift of the maxima at 284 and 294 m/x, in comparison with those of 4-methoxy-l-methyl-2-quinolone (268 and 278 m/a), can be attributed... 

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