- Synthesis of Novel Ciprofloxacin-Based Hybrid Molecules toward Potent Antimalarial Activity
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Antimalarial drug resistance is a serious obstacle in the persistent quest to eradicate malaria. There is a need for potent chemical agents that are able to act on drug-resistant Plasmodium falciparum populations at reasonable concentrations without any related toxicity to the host. By rational drug design, we envisaged to address this issue by generating a novel hybrid drug possessing two pharmacophores that can act on two unique and independent targets within the cell. We synthesized a new class of ciprofloxacin-based hybrid molecules, which have been integrated with acridine, quinolone, sulphonamide, and cinnamoyl pharmacophores (1-4). We realized a potent chloroquinolone-ciprofloxacin-based antimalarial hybrid (2, CQ-CFX) whose mechanism of action is unlike that of its parent molecules indicating a unique biological target. CQ-CFX is not only potent against CQ-resistant and susceptible strains of Plasmodium falciparum at low nanomolar concentrations (IC50 values are 63.17 ± 1.2 nM and 25.52 ± 4.45 nM, respectively) but is also not toxic to mammalian and bacterial systems up to 20 μM and 1 μM, respectively.
- Dana, Srikanta,Dhar, Suman Kumar,Gurung, Sumiran Kumar,Kumar, Sharvan,Mondal, Neelima,Mukhopadhyay, Pritam,Valissery, Praveesh
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p. 1450 - 1456
(2020/08/14)
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- NEXT-GENERATION MODULATORS OF STIMULATOR OF INTERFERON GENES (STING)
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The present invention relates to compounds of formula (I) and salts, stereoisomers, tautomers or N-oxides thereof that are useful as modulators of STING (Stimulator of Interferon Genes). The present invention further relates to the compounds of formula (I) for use as a medicament and to a pharmaceutical composition comprising said compounds.
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Page/Page column 67-68
(2020/12/30)
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- A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide
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Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization's Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.
- Tosso, N. Perrer,Desai, Bimbisar K.,De Oliveira, Eliseu,Wen, Juekun,Tomlin, John,Gupton, B. Frank
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p. 3370 - 3376
(2019/03/11)
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- Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones
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The advantageous use of ionic liquids (ILs) as alternatives to common DMF as solvent in the Grohe cycloaracylation for the synthesis of pharmaceutically relevant quinolones is reported. ILs showed in many cases shorter reaction times and higher yields, complete conversions of the reactants and easy work-up procedures compared with DMF. Of the ILs screened, tributylmethylammonium methanesulfonate ([TBMA][MsO]) was selected as the most suitable for further studies. Interestingly, a wide substrate scope was observed and the IL was recycled by a green process. A further step forward in the use of [TBMA][MsO] for quinolone synthesis was the preparation by a one-pot/three-step procedure of the representative 3-carboxy-4-quinolone acid 16, which was obtained in high yield in a short time. The greener properties of ILs in comparison with DMF and their non-volatility appoint this method as a potentially efficient and alternative approach to the industrial production of quinolones.
- Cannalire, Rolando,Tiecco, Matteo,Cecchetti, Violetta,Germani, Raimondo,Manfroni, Giuseppe
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p. 2977 - 2983
(2018/06/27)
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- STREAMLINED SYNTHESES OF FLUOROQUINOLONES
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Methods of synthesizing fluoroquinolones such as ciprofloxacin are provided. The methods utilize affordable materials, reduce the number of synthesis steps and provide high yields.
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Page/Page column 16; 28-30; 33; 34-35
(2019/01/08)
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- ANTIBIOTIC RESISTANCE BREAKERS
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The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
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Page/Page column 95
(2019/01/05)
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- Method for efficiently and environmentally friendly preparing quinolones
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The invention discloses a method for efficiently and environmentally friendly preparing quinolones. Fluorobenzoylacetic acid ethyl ester, triethyl orthoformate and amine compounds are used as raw materials, and the quinolones are synthesized by maintainin
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Paragraph 0024
(2019/01/05)
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- A Rapid Total Synthesis of Ciprofloxacin Hydrochloride in Continuous Flow
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Within a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine.
- Lin, Hongkun,Dai, Chunhui,Jamison, Timothy F.,Jensen, Klavs F.
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supporting information
p. 8870 - 8873
(2017/07/17)
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- Novel fluoroquinolones and use thereof to treat bacterial infections
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The present invention relates to novel fluoroquinolones possessing a piperazine moiety substituted by a long alkyl chain, pharmaceutical compositions or medicament containing them and use thereof to treat bacterial infection.
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Paragraph 0053; 0057-0059
(2016/01/12)
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- Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis
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Novel 3′-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by 1H, 13C and 19F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC50), or inducing 25% DNA cleavage by DNA gyrase (CC25). Compound 4 (with a methoxy in R8 and a secondary carbamate in R3′) and compound 5 (with a hydrogen in R8 and an ethyl ester in R3′) displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R3′ substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.
- Gomez, Catherine,Ponien, Prishila,Serradji, Nawal,Lamouri, Aazdine,Pantel, Alix,Capton, Estelle,Jarlier, Vincent,Anquetin, Guillaume,Aubry, Alexandra
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p. 948 - 956
(2013/03/13)
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- ANTIBACTERIAL COMPOUNDS
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The present Invention relates to cephalosporin antibacterial compounds of Formula (!): corresponding pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, compound preparation and treatment methods for bacterial infections, especially those caused by gram-negative bacteria.
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- Enhancement of the antimalarial activity of ciprofloxacin using a double prodrug/bioorganometallic approach
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The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining bioorganometallic chemistry and the prodrug approach. Two new achiral compounds 2 and 4 were found to be 10- to 100-fold more active than ciprofloxacin against Plasmodium falciparum chloroquinesusceptible and chloroquine-resistant strains. These achiral derivatives killed parasites more rapidly than did ciprofloxacin. Compounds 2 and 4 were revealed to be promising leads, creating a new family of antimalarial agents.
- Dubar, Faustine,Anquetin, Guillaume,Pradines, Bruno,Dive, Daniel,Khalife, Jamal,Biot, Christophe
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supporting information; experimental part
p. 7954 - 7957
(2010/08/13)
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- PROCESSES FOR PREPARING QUINOLONECARBOXYLATE DERIVATIVES
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The present invention provides a process for preparing quinolonecarboxylate derivatives under a mild condition in high yield, so as to be favorably applied to a large-scale mass production thereof.
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- Microreaction technology as a novel approach to drug design, process development and reliability
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This paper focuses on the application of microreaction technology in the life science industry. Certain features of microreaction technology, for example, mixing, heat transfer, and residence time distribution, are discussed. Important advantages such as high operational safety and the possibility to transfer the experimental results directly from laboratory to the production of pilot-plant scales are mentioned. Potential application fields in the drug discovery and development processes, from research to production, by including chemical synthesis of different targets in the case of the quinoline acid derivative (ciprofloxacin) and the Paal - Knorr pyrrole synthesis are presented.
- Taghavi-Moghadam, Shahriyar,Kleemann, Axel,Golbig, Klaus Georg
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p. 652 - 658
(2013/09/07)
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- 7-(substituted)piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
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7-(substituted)piperazinyl-1-ethyl-6-fluoro-4-oxo-3-quinolinecarboxylic acids, the pharmacologically acceptable salts thereof, compositions containing them, processes and intermediates for producing them, and methods of using them to treat bacterial infections in warm-blooded animals.
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- Intermediates for preparing 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid esters
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Compounds of the formula: wherein Y is OR1, fluoro, chloro, methyl, R1, and R3 are independently selected from hydrogen and C1-C4 alkyl, R2 is C1-C4 alkyl and X is fluoro, chloro or bromo, with the proviso that when Y is OH, X cannot be bromo and with the proviso that X can be fluoro only if R2 is methyl.
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- Antibacterial agents
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Novel naphthyridine-, and quinolinecarboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections including the description of certain novel intermediates used in the
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- Process for preparing 2-chloro-4,5-difluorobenzoic acid
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This disclosure describes a novel process for preparing 2-chloro-4,5-difluorobenzoic acid which is useful in the preparation of 7-(substituted)piperazinyl-1-substituted-6-fluoro-1,4-dihydro-4-oxo-3-quinoli necarboxylic acid antibacterial agents.
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- Quinolone Antibacterial Agents. Synthesis and Structure-Activity Relationships of 8-Substituted Quinoline-3-carboxylic Acids and 1,8-Naphthyridine-3-carboxylic Acids
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A series of 7,8-disubstituted 1-cyclopropyl-6-fluoroquinoline-3-carboxylic acids, 7-substituted 1-cyclopropyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids, and 10-substituted 9-fluoropyridobenzoxazine-6-carboxylic acids has been prepared and evaluated for antibacterial activity.The side chains examined at the 7-position (benzoxazine 10-position) included piperazinyl (g), 3-aminopyrrolidinyl (a), 3-(aminomethyl)pyrrolidinyl (b), and alkylated 3-(aminomethyl)pyrrolidinyl (c-f).Variations ta C-8 of the quinolone ring system included hydrogen, nitro, amino, fluorine and chlorine.The relative enhancement of in vitro activities by the side chains on the 8-hydrogen quinolone and 1,8-naphthyridine against Gram-negative organisms was a > b > g > c-f.The activity imparted to the substituted quinolone nucleus by the 8-substituent was in the order F > Cl > naphthyridine > H > benzoxazine > NH2 > NO2.These trends were retained in vivo.
- Sanchez, Joseph P.,Domagala, John M.,Hagen, Susan E.,Heifetz, Carl L.,Hutt, Marland P.,et al.
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p. 983 - 991
(2007/10/02)
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- Cycloaracylation of Enamines, I. - Synthesis of 4-Quinolone-3-carboxylic Acids
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Starting with o-halobenzoyl chlorides 4 and open-chain secondary enamines 5, a new synthesis of 4-quinolone-3-carboxylic acids 12 is described.The reaction of 7-haloquinolone-3-carboxylic acids 12a-k with aliphatic amines 14 produces highly active antibacterial 7-aminoquinolone-3-carboxylic acids 15.The main product of the 1-cyclopropyl series, "ciprofloxacin" (15a), is being developed as a broad-spectrum chemotherapeutic agent.
- Grohe, Klaus,Heitzer, Helmut
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