- A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae
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Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.
- Wang, Xu,Zeng, Yuna,Sheng, Li,Larson, Peter,Liu, Xue,Zou, Xiaowen,Wang, Shufang,Guo, Kaijing,Ma, Chen,Zhang, Gang,Cui, Huaqing,Ferguson, David M.,Li, Yan,Zhang, Jingren,Aldrich, Courtney C.
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p. 2305 - 2332
(2019/04/25)
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- Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts in the One-Step Isomerisation of Cinchona Alkaloids to Δ3,10-Isobases
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Abstract: Efficiency of palladium solid supported (Pd/SS) catalysts for one-step isomerisation of the side chain of four natural Cinchona alkaloids have been explored under controlled microwave heating in the green media (50% aqueous ethanol or ethylene g
- Lipińska, Teodozja M.,Borowska, Dominika,Sw?dra, Natalia,Trochim, Katarzyna
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p. 2835 - 2843
(2017/09/14)
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- Hydrogenation of prochiral ketones
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Process for enantioselectively hydrogenating prochiralen ketones to (S)-alcohols using platinum catalysts in the presence of cinchonines or quinidines as modifiers and in the presence of hydrogen, which is characterized in that the modifiers used are cinchonines unsubstituted in the 3-position, 3-ethylidenyl- or 9-methoxycinchonines or derivatives thereof in which the quinoline ring is replaced by other rings.
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Page/Page column 6
(2010/01/31)
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- Positional isomerization of quinine and quinidine via rhodium on alumina catalysis: Practical one-step synthesis of Δ3,10-isoquinine and Δ3,10-isoquinidine
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The synthesis of Δ3,10-isoquinine (5Z,5E) and Δ3,10-isoquinidine (6Z,6E) was achieved in one-step through positional isomerization of the terminal alkene in the parent cinchona alkaloids using catalytic amounts of 5% Rh/Al2O3 and excess hydrochloric acid in refluxing 50% aqueous EtOH. The products were obtained in good yields as a mixture of E and Z geometric isomers and fully characterized using spectroscopic methods.
- Portlock, David E.,Naskar, Dinabandhu,West, Laura,Seibel, William L.,Gu, Titan,Krauss, Howard J.,Peng, X. Sean,Dybas, Paul M.,Soyke, Edward G.,Ashton, Stephen B.,Burton, Jonathan
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p. 5365 - 5368
(2007/10/03)
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- Heterogeneous Enantioselective Hydrogenation of Activated Ketones Catalyzed by Modified Pt-Catalysts: A Systematic Structure-Selectivity Study
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A systematic structure-selectivity study was carried out for the enantioselective hydrogenation of activated ketones with chirally modified Pt/Al2O3 catalysts. For this, 18 modifiers containing an extended aromatic system able to form a strong adsorption complex with the Pt surface, and a suitable chiral group with an amino function capable to interact with the keto group of the substrate (HCd, Qd, HCn, Qn, and semi-synthetic derivatives, as well as synthetic analogues) were prepared and tested on 8 different activated ketones in AcOH and toluene under standard conditions. It was found that relatively small structural changes of the substrate and/or modifier structures strongly affected the enantioselectivity, and that no "best" modifier exists for all substrates. The highest ees for all substrates were obtained with quinuclidine-derived modifiers in combination with naphthalene or quinoline rings, either in AcOH (substrates 1-5 and 8, all carrying an sp3 carbon next to the keto group) or toluene (6 and 7, with an sp2 carbon next to the ketone). The presence and nature of the substituent R′ at the quinuclidine significantly affected the ee (positive and negative effects). Certain combinations of an aromatic system and an amino function were preferred: For the quinuclidine moiety, quinoline and to a somewhat lesser extent naphthalene were a better match, while for the pyrrolidinylmethyl group anthracene was better suited. Methylation of the OH group often had a positive effect for hydrogenations in AcOH but not in toluene. With the exception of 8, higher ees were obtained for the Cd/ Qn series [leading to (R)-products] than for the Cn/ Qd series [leading to (S)-products]. In several cases, opposite structure-selectivity trends were detected when comparing reactions in toluene and AcOH, indicating a significant influence of the solvent.
- Exner, Christian,Pfaltz, Andreas,Studer, Martin,Blaser, Hans-Ulrich
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p. 1253 - 1260
(2007/10/03)
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- Hydrogenation of prochiral ketones
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Process for enantioselectively hydrogenating prochiralen ketones to (S)-alcohols using platinum catalysts in the presence of cinchonines or quinidines as modifiers and in the presence of hydrogen, which is characterized in that the modifiers used are cinchonines unsubstituted in the 3-position, 3-ethylidenyl- or 9-methoxycinchonines or derivatives thereof in which the quinoline ring is replaced by other rings.
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Page/Page column 9
(2010/11/29)
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- Asymmetric conversions of 10-bromo-10,11-dihydroquinines into 8-oxa-1-azabicyclo[4.3.0]nonane derivatives and related compounds
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Some transformations of (10R)- and (10S)-bromo-10,11-dihydroquinine 2a and 2b have been investigated in order to obtain insights into their unexplored chirality. The (10R)-diastereomer 2a converts stereoselectively into (4S)-(E-propenyl)-(6S,7R)-(6-methoxy-quinol-4-yl)-8-oxa-(1R)-azabicyclo [4.3.0]nonane 10, which is the product of a novel rearrangement of the parent quinine 1 and displays the N(1)-(S)-configuration (10a) in the solid state. The (10S)-diastereomer 2b afforded 10 and its (Z)-propenyl isomer 15 (in the ratio 55:45), as well as (Z)-3,10-didehydro-10,11-dihydro-quinine 19. On treatment with acid the alkaloid 10 yields [(4S)-(E)-propenyl)-(2S)-piperidinyl]-6-methoxyquinoline-(αR)-methanol 12. Closure of the oxazolidine ring in 12 gives 14, the 9,9-dimethyl-derivative of 10, with the N(1) configuration inverted. The molecular structures of 10a and 14, determined by X-ray diffraction, show their similar conformations except for the axial (E)-propenyl substituent, disordered in two orientations in 10a and ordered in another position in 14.
- Thiel, Jacek,Katrusiak, Andrzej
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- (3S)-3-Hydroxyquinidine, the Major Biotransformation Product of Quinidine. Synthesis and Conformational Studies. X-Ray Molecular Structure of (3S)-3-Hydroxyquinidine Methanesulphonate
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(3S)-3-Hydroxyquinidine, the major metabolite of the Cinchona alkaloid quinidine, was prepared by synthetic chemical modification or microbial oxidation of quinidine.The structure of this metabolite has been demonstrated to be (3S)-3-hydroxyquinidine by 1H and 13C NMR, IR, UV and mass spectral analysis.Previously published comparisons of the 13C NMR spectra of 3-hydroxyquinidine and model compounds were used to establish the absolute stereochemistry of the metabolite (see ref. 8).This assignment has been verified by single-crystal X-ray analysis of (3S)-3-hydroxyquinidine methanesulphonate.The gas- and solution-phase conformational preference of the metabolite derived from molecular modelling and NOE studies are compared with the conformation observed by X-ray crystallography.
- Carroll, F. Ivy,Abraham, Philip,Gaetano, Kevan,Mascarella, S. Wayne,Wohl, Ronald A.,et al.
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p. 3017 - 3026
(2007/10/02)
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