- Asymmetric Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride
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The asymmetric (er > 99:1) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that is accessed in three steps from commercially available materials, making the overall synthetic sequence very concise. The common diol intermediate derived from the Sharpless asymmetric dihydroxylation is converted into either a trans- or cis-epoxide, and these are subsequently converted to (+)-anti- and (-)-syn-mefloquine, respectively. X-ray crystallographic analysis of derivatives of (+)-anti- and (-)-syn-mefloquine is used to lay to rest a 40 year argument regarding the absolute stereochemistry of the mefloquines. A formal asymmetric (er > 99:1) synthesis of (+)-anti-mefloquine hydrochloride is also presented that uses a Sharpless asymmetric epoxidation as a key step.
- Rastelli, Ettore J.,Coltart, Don M.
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Read Online
- Application of 2, 8-bis (trifluoromethyl)-4-hydroxyquinoline derivative in preparation and prevention and treatment of agricultural diseases
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The invention discloses application of a 2, 8-bis (trifluoromethyl)-4-hydroxyquinoline derivative in preparation and prevention and treatment of agricultural diseases. Activity test results show that the compound has potential inhibitory activity on four plant pathogenic fungi including sclerotinia sclerotiorum, botrytis cinerea, fusarium graminearum and rhizoctonia solani, and can be developed as a bactericide.
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Paragraph 0355-0358; 0499-0502
(2021/04/07)
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- Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids
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Enlightened from our previous work of structural simplification of quinine and innovative application of natural products against phytopathogenic fungi, lead structure 2,8-bis(trifluoromethyl)-4-quinolinol (3) was selected to be a candidate and its diversified design, synthesis, and antifungal evaluation were carried out. All of the synthesized compounds Aa1-Db1 were evaluated for their antifungal activity against four agriculturally important fungi, Botrytis cinerea, Fusarium graminearum, Rhizoctonia solani, and Sclerotinia sclerotiorum. Results showed that compounds Ac3, Ac4, Ac7, Ac9, Ac12, Bb1, Bb10, Bb11, Bb13, Cb1. and Cb3 exhibited a good antifungal effect, especially Ac12 had the most potent activity with EC50 values of 0.52 and 0.50 μg/mL against S. sclerotiorum and B. cinerea, respectively, which were more potent than those of the lead compound 3 (1.72 and 1.89 μg/mL) and commercial fungicides azoxystrobin (both >30 μg/mL) and 8-hydroxyquinoline (2.12 and 5.28 μg/mL). Moreover, compound Ac12 displayed excellent in vivo antifungal activity, which was comparable in activity to the commercial fungicide boscalid. The preliminary mechanism revealed that compound Ac12 might cause an abnormal morphology of cell membranes, an increase in membrane permeability, and release of cellular contents. These results indicated that compound Ac12 displayed superior in vitro and in vivo fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.
- Chen, Yong-Jia,Ma, Kun-Yuan,Du, Sha-Sha,Zhang, Zhi-Jun,Wu, Tian-Lin,Sun, Yu,Liu, Ying-Qian,Yin, Xiao-Dan,Zhou, Rui,Yan, Yin-Fang,Wang, Ren-Xuan,He, Ying-Hui,Chu, Qing-Ru,Tang, Chen
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p. 12156 - 12170
(2021/10/26)
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- Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity
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Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.
- Agnamey, P.,Azas, N.,Cohen, A.,Damiani, C.,Dassonville-Klimpt, A.,Dormoi, J.,Guillon, J.,Marchivie, M.,Pradines, B.,Schneider, J.,Sonnet, P.,Taudon, N.,Tisnerat, C.,Totet, Anne,Mullié, C.
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- Synthesis and study of new quinolineaminoethanols as anti-bacterial drugs
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The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines 3, which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) bacteria. Secondly, a new series 4 was designed and assessed against the same bacteria strains, taking the pair of enantiomers 3m/3n as the lead. More than twenty compounds 4 were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series 3 were efficient on M. avium with MIC = 2–16 μg/mL, while series 4 was less active. Both series 3 and 4 were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines 4 were either active against Gram-positive bacteria (MIC ≤ 4 μg/mL for 4c–4h and 4k/4l) or E. coli (MIC = 32–64 μg/mL for 4q–4v) according to the global lipophilicity of these compounds.
- Laumaillé, Pierre,Dassonville-klimpt, Alexandra,Peltier, Fran?ois,Mullié, Catherine,Andréjak, Claire,Da-nascimento, Sophie,Castelain, Sandrine,Sonnet, Pascal
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- A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines
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A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+)-mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine.
- Rastelli, Ettore J.,Coltart, Don M.
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supporting information
p. 14070 - 14074
(2016/01/25)
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- 4-AMINOALCOHOLQUINOLINE DERIVATIVES, ENANTIOSELECTIVE SYNTHESIS METHODS AND THE USE THEREOF
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The present invention is intended to provide new antimalarial compounds with a strong antimalarial activity as well as antibacterial activity with few neurological side effects and a new enantioselective pathway to mefloquine amino-analogs allowing the access of such compounds. The present invention relates to new 4 -aminoalcohol quinoline derivatives of formula (I), as well as the synthesis methods and the uses of such derivatives. In which Y is one selected from formulae (II) to (III). In which Z is selected from formulae (IV) to (VI), and wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined in the claims.
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Page/Page column 20-21
(2012/08/28)
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- Enantioselective synthesis method of 4-aminoalcoholquinoline derivatives and the use
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Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Although mefloquine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer is more potent than the (-)-enantiomer. Moreover, the (-)-enantiomer is responsible for side effects due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does no bind at this binding site. Recently, different libraries of racemate 4-aminoalcoholquinolines showed interesting anti-malarial activities. Herein, the present invention describes an enantiopure synthetic and straightforward route to prepare pure enantiomer 4-aminoalcoholquinoline derivatives through the 4-oxirane key-intermediate. A regioselective SN2 ring opening of this epoxide, by diverse amines, allows to obtain the corresponding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantiomer 4-aminoalcoholquinoline derivatives.
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Page/Page column 12
(2012/08/28)
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- First enantioselective synthesis of 4-aminoalcohol quinoline derivatives through a regioselective SN2 epoxide opening mechanism
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Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Although mefloquine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer is more potent than the (-)-enantiomer. Moreover, the (-)-enantiomer is responsible for side effects due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does no bind at this binding site. Recently, different libraries of racemic 4-aminoalcohol quinolines showed interesting antimalarial activities. Herein, we describe an enantiopure synthetic and straightforward route to prepare pure enantiomer 4-aminoalcohol quinoline derivatives through a 4-oxirane key-intermediate. A regioselective SN2 ring opening of this epoxide, by diverse amines, allows us to obtain the corresponding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantiomer 4-aminoalcohol quinoline derivatives.
- Jonet, Alexia,Dassonville-Klimpt, Alexandra,Da Nascimento, Sophie,Leger, Jean-Michel,Guillon, Jean,Sonnet, Pascal
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experimental part
p. 138 - 148
(2011/05/02)
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- Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against plasmodium falciparum
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A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC90) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8- bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.
- Milner, Erin,Gardner, Sean,Moon, Jay,Grauer, Kristina,Auschwitz, Jennifer,Bathurst, Ian,Caridha, Diana,Gerena, Lucia,Gettayacamin, Montip,Johnson, Jacob,Kozar, Michael,Lee, Patricia,Leed, Susan,Li, Qigui,McCalmont, William,Melendez, Victor,Roncal, Norma,Sciotti, Richard,Smith, Bryan,Sousa, Jason,Tungtaeng, Anchalee,Wipf, Peter,Dow, Geoffrey
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supporting information; experimental part
p. 6277 - 6285
(2011/11/05)
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- Structure-activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum
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Utilizing mefloquine as a scaffold, a next generation quinoline methanol (NGQM) library was constructed to identify early lead compounds that possess biological properties consistent with the target product profile for malaria chemoprophylaxis while reducing permeability across the blood-brain barrier. The library of 200 analogs resulted in compounds that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum. Herein we report selected chemotypes and the emerging structure-activity relationship for this library of quinoline methanols.
- Milner, Erin,McCalmont, William,Bhonsle, Jayendra,Caridha, Diana,Carroll, Dustin,Gardner, Sean,Gerena, Lucia,Gettayacamin, Montip,Lanteri, Charlotte,Luong, ThuLan,Melendez, Victor,Moon, Jay,Roncal, Norma,Sousa, Jason,Tungtaeng, Anchalee,Wipf, Peter,Dow, Geoffrey
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supporting information; experimental part
p. 1347 - 1351
(2010/07/02)
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- Synthesis of quinoline analogs: Search for antimalarial agents
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Novel synthesis routes for the promising antimalarial agents 4(3-hydroxypyrrolidin-1-yl) and 4(3-hydroxypiperidine-1-yl)-2,8- bis(trifluoromethyl)quinoline have been developed.
- Babu, Konda Ramesh,Eeshwaraiah, Begari,Aravind, Dachepally,Meshram, Harshadas M.,Raju, Rallabaldi Madhusudan,Bhattacharya, Apurba,Bandichhor, Rakeshwar
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p. 179 - 181
(2008/09/20)
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