- Fluorine walk: The impact of fluorine in quinolone amides on their activity against African sleeping sickness
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Human African Trypanosomiasis, also known as African sleeping sickness, is caused by the parasitic protozoa of the genus Trypanosoma. If there is no pharmacological intervention, the parasites can cross the blood-brain barrier (BBB), inevitably leading to death of the patients. Previous investigation identified the quinolone amide GHQ168 as a promising lead compound having a nanomolar activity against T. b. brucei. Here, the role of a fluorine substitution at different positions was investigated in regard to toxicity, pharmacokinetics, and antitrypanosomal activity. This ‘fluorine walk’ led to new compounds with improved metabolic stability and consistent activity against T. b. brucei. The ability of the new quinolone amides to cross the BBB was confirmed using an 18F-labelled quinolone amide derivative by means of ex vivo autoradiography of a murine brain.
- Berninger, Michael,Erk, Christine,Fu?, Antje,Skaf, Joseph,Al-Momani, Ehab,Israel, Ina,Raschig, Martina,Güntzel, Paul,Samnick, Samuel,Holzgrabe, Ulrike
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supporting information
p. 377 - 391
(2018/05/22)
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- An efficient reduction of azide to amine: A new methodology to synthesize ethyl 7-amino-1-ethyl-6,8-difluoroquinolone-3-carboxylate and its spectroscopic characterization
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Most of the quinolone antibacterial research has been focused on the functionality at C-7 position where the nature of substituents is responsible for antibacterial spectrum, potency, bioavailability, and side effects of the quinolones. Then, a 7-amino-fluoroquinolone could be the starting point of a wide variety of potentially useful compounds like tetracyclic and tricyclic quinolones or secondary amines with side chain derivatives. This attracted our attention to synthesize a 7-azide-fluoroquinolone, which could be converted to amine performing a photochemical reaction using CuI as catalyst. FT-IR and H1 NMR spectra of the final product, ethyl 7-amino-1-ethyl-6,8-difluoroquinolone-3-carboxylate, suggests the formation of dimers, a feature already observed in norfloxacin.
- Leyva-Ramos, Socorro,Hernández-López, Hiram,Jiménez-Cata?o, Rogelio,Chacón-García, Luis,Vega-Rodríguez, Sarai
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p. 939 - 947
(2017/05/01)
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- Novel Glycoconjugate of 8-Fluoro Norfloxacin Derivatives as Gentamicin-resistant Staphylococcus aureus Inhibitors: Synthesis and Molecular Modelling Studies
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Antibiotic resistance has been the subject of interest in clinical practice due to high prevalence of antibiotic-resistant pathogenic organisms. In view of the prevalence of lesser resistance in antibiotics belonging to aminoglycoside class of compounds viz. Food and Drug Administration-approved gentamicin for the treatment of Staphylococcus infections, which also has instances of resistance in the clinical isolates of Staphylococcus aureus, a series of novel glycoconjugates of 8-fluoro norfloxacin analogues with high regio-selectivity by employing copper (I)-catalyzed 1, 3-dipolar cycloaddition of 1-O-propargyl monosaccharides has been synthesized and evaluated for the antibacterial activity against gentamicin resistance Staphylococcus aureus. Among these compounds, the compound 10g showed better antibacterial activity (MIC = 3.12 μg/ml) than gentamicin (Escherichia coli (12.5 μg/ml), Staphylococcus aureus (6.25 μg/ml) and Klebsiella pneumonia (6.25 μg/ml), including gentamicin resistant (>50 μg/ml) strain in vitro). The docking studies suggest DNA gyrase of Staphylococcus aureus as a probable target for the antibacterial action of compound 10g.
- Azad, Chandra S.,Bhunia, Shome S.,Krishna, Atul,Shukla, Praveen K.,Saxena, Anil K.
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p. 440 - 446
(2015/02/19)
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- Photochemistry of some non zwitterionic fluoroquinolones
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Two non zwitterionic analogues of fluoroquinolone drugs, viz. 1-ethyl-7-piperidino-8-fluoroquinol-4- one-3-carboxylic acid and 1-ethyl-7-piperidino-6,8-difluoroquinol-4-one-3-carboxylic acids have been synthesized and their photochemistry has been investigated. Both compound undergo photoheterolysis of the C8 F bond generating a triplet cation that either inserts into the 1-alkyl chain or is trapped or reduced by external nucleophiles. The reaction is analogous to that observed with the corresponding (zwitterionic) 7-piperazino derivatives, but the quantum yield is ca five times lower. This supports the rationalization that in the latter case assistance to defluorination by the N+ H bond has a determining role.
- Dichiarante, Valentina,Pretali, Luca,Fasani, Elisa,Albini, Angelo
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- Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics
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The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC50 = 36 nM, EC50 = 3.2 μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.
- Seto, Shigeki,Yumoto, Kazuhiko,Okada, Kyoko,Asahina, Yoshikazu,Iwane, Aya,Iwago, Maki,Terasawa, Reiko,Shreder, Kevin R.,Murakami, Koji,Kohno, Yasushi
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p. 1188 - 1200
(2012/03/26)
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- Synthesis and antibacterial evaluation of novel 8-fluoro Norfloxacin derivatives as potential probes for methicillin and vancomycin-resistant Staphylococcus aureus
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A series of novel 8-fluoro Norfloxacin derivatives and the hybrids of its piperazinyl derivatives incorporated with 1,3,5-triazine and pyrimidine were synthesized. All the above compounds were evaluated for their antibacterial activity against Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus and methicillin & vancomycin-resistant S. aureus. Among all, compounds having Morpholine, N-methyl/phenyl/benzyl/pyrimidinyl piperazines and n-butylamine substitution at C-7 position, have shown increased potency in comparison to norfloxacin and ciprofloxacin.
- Sunduru, Naresh,Gupta, Leena,Chauhan, Kuldeep,Mishra, Nripendra N.,Shukla, Praveen K.,Chauhan, Prem M.S.
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experimental part
p. 1232 - 1244
(2011/04/22)
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- Synthesis and in vitro antimicrobial evaluation of novel fluoroquinolone derivatives
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A series of 1-ethyl-6,8-difluoro-4-oxo-7(4-aryl piperazin-1-yl) 1,4-dihydro-quinoline-3-carboxylic acid derivatives (6a-f) and 1-ethyl-6,8-difluoro-4-oxo-7(4-piperidin-1-yl) 1,4-dihydro-quinoline-3- carboxylic acid derivatives (7a-e) were synthesized and evaluated for antibacterial and antifungal activities. The antimicrobial activities of the compounds were assessed by the microbroth dilution technique. The compounds were also evaluated for antifungal activity against Candida albicans (ATCC 90028) and Cryptococcous neoformans (ATCC 14116) pathogens. The preliminary in vitro evaluation studies revealed that some of the compounds have promising antimicrobial activities.
- Srinivasan, Shanmugam,Beema Shafreen, Raja Mohmed,Nithyanand, Paramasivam,Manisankar, Paramasivam,Pandian, Shunmugiah Karutha
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experimental part
p. 6101 - 6105
(2011/01/13)
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- Microwave-assisted simple synthesis of substituted 4-quinolone derivatives
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A simple and efficient method was developed for the synthesis of 4-quinolone-3-carboxylic esters and 4-quinolone-3-carbonitriles under microwave (MW) activation using anilines and acrylates as materials. All reactions demonstrated the benefits of microwave reactions: convenient operation, short reaction time, and good yields.
- Cao, Xin,You, Qi-Dong,Li, Zhi-Yu,Yang, Yan,Wang, Xiao-Jian
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experimental part
p. 4375 - 4383
(2010/05/01)
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- Synthesis of new quinolone antibiotics utilizing azetidine derivatives obtained from 1-azabicyclo[1.1.0]butane
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A series of 3-sulfenylazetidine derivatives 5a-f were synthesized via the ring-opening reactions of 1-azabicyclo[ 1.1.0]butane (ABB, 3) with thiols 4a-f in 50-92% yields. Treatment of ABB (3) with aromatic amines 9a-e and dibenzylamine (9f) in the presence of Mg(ClO4)2 afforded the corresponding 3-aminoazetidine derivatives 10a-f in 24-65% yields. N-Benzyl-3-bromoazetidine (13), which was obtained by the reaction of ABB (3) with benzyl bromide, gave 3-aliphatic amino-substituted azetidine derivatives 15a, b. Novel fluoroquinolones 7a-f, 11a-f, 16a, b and 25a-c were obtained by the introduction of these azetidine derivatives into the C7 position of a quinolone nucleus 6 and N1-heterocyclic quinolones 21a-c in 21-83% yields. Some of them exhibited a greater antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in comparison with that of clinically used fluoroquinolone, levofloxacin (LVFX).
- Ikee, Yoshifumi,Hashimoto, Kana,Kamino, Mai,Nakashima, Masaaki,Hayashi, Kazuhiko,Sano, Shigeki,Shiro, Motoo,Nagao, Yoshimitsu
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p. 346 - 356
(2008/12/22)
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- Thermochemical reaction of 7-azido-1-ethyl-6,8-difluoroquinolone-3-carboxylate with heterocyclic amines. An?expeditious synthesis of novel fluoroquinolone derivatives
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Novel 7-hydrazino-1-ethyl-6,8-difluoroquinolone-3-carboxylate derivatives are obtained by thermochemical reaction of 7-azido-1-ethyl-6,8-difluoroquinolone-3-carboxylate with heterocyclic amines. These new fluoroquinolone carboxylates could be used as precursors in the preparation of novel fluoroquinolone carboxylic acids. These latter compounds are known to have biological activity.
- Leyva, Socorro,Leyva, Elisa
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p. 2093 - 2097
(2007/10/03)
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- QUINOLONE DERIVATIVE OR SALT THEREOF
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A platelet aggregation inhibitor comprising a quinolone derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a novel quinolone derivative or a pharmaceutically acceptable salt thereof useful as a platelet aggregation inhibitor.
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Page/Page column 21-22
(2008/06/13)
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- An NMR study of halogenated 1,4-dihydro-1-ethyl-4-oxoquinoline-3-carboxylates
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Ethyl 1,4-dihydro-1-ethyl-4-oxoquinoline-3-carboxylate and 29 of its mono-, di-and tri-fluoro and/or -chloro derivatives were synthesized and their 1H, 13C and 19F NMR spectra were recorded. 1H, 13C and 19F chemical shifts, JHH, JFH, JCF and JFF coupling constants are reported. The 13C substituent chemical shift values of the chloro and fluoro substituents were calculated by linear multiple regression.
- Podanyi, Benjamin,Kereszturi, Geza,Vasvari-Debreczy, Lelle,Chinoin, Istvan Hermecz,Toth, Gabor
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p. 972 - 978
(2007/10/03)
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- STUDIES DIRECTED TOWARDS NOVEL PENEM ANTIBACTERIALS
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The reaction of 2-thioxopenam esters with hydroxylamine-O-sulfonic acid leads to stable 2-sulfeneamide penem esters that do not cyclize to give the corresponding isothiazolinones.
- Phillips, J. G.,Chu, D.,Spanton, S.,Henry, R.,Plattner, J. J.
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p. 3733 - 3736
(2007/10/02)
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- Tautomerism and acidity in 4-quinolone-3-carboxylic acid derivatives
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Prototropic tautomerism in 4-quinolone-3-carboxylic acid derivatives has been studied with particular emphasis on the influence of the ring substituents on the equilibrium. The techniques used include UV, 1H-NMR, 13C-NMR (solution and 13C-NMR CP/MAS (solid state) and semiempirical and ab initio calculations. The pKa values of some quinolone derivatives have been determined and correlated with data obtained from semiempirical methods.
- De La Cruz, Angeles,Elguero, Jose,Goya, Pilar,Martinez, Ana,Pfleiderer, Wolfgang
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p. 6135 - 6150
(2007/10/02)
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- 4-Hydroxy-quinoline-3-carboxylic
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A process for the preparation of a compound of the formula STR1 in which Y is a nitrile group, an ester group COOR1 or an acid amide CONR2 R3, R1, R2 and R3 each independently is hydrogen or C1 -C4 -alkyl, and R3 may also be phenyl, and X2, X3, X4 and X5 each independently is hydrogen, halogen, nitro, cyano, alkyl having 1-3 carbon atoms, alkoxy having 1-3 carbon atoms, alkylmercapto having 1-3 carbon atoms, alkylsulphonyl having 1-3 carbon atoms, or a phenylsulphonyl group which is optionally substituted in the aryl radical, comprising reacting an aminoacrylate of the formula in which X1 is halogen, a nitro group, an alkoxy, alkoxy, alkylmercapto or alkylsulphonyl group having 1-3 carbon atoms in each case, or an arylsulphonyl group, W is hydrogen or a --CH2 CH2 Z radical, Z is is a nitrile group, an ester group COOR4 or an acid amide group CONR5 R6, and R4, R5 and R6 each independently is hydrogen or C1 -C4 -alkyl, and R5 may also be phenyl, with an acid acceptor in an aprotic solvent. Some of the reactants are new, as are the products which are intermediates for antibacterially active 1-alkyl-4-quinolone-3-carboxylic acids.
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