Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, optical purity, and absolute stereochemistry

Carroll, F. Ivy; Blackwell, J. T.

doi:10.1021/jm00248a015

Cited by 84 publications

(50 citation statements)

References 5 publications

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“…N-Acetylephedrine (2) crystal which we managed to obtain from aqueous solution contained only one kind of conformer in the elementary cell. No other conformer was found to be present in solution, and this was corroborated by NMR spectra, both in this study and in [24,25]. The hydroxyl group in compound 2 played a fundamental role in the arrangement of particular molecular fragments relative to one another, which is likely of importance to the packing of molecules in the elementary cell.…”

Section: X-ray Analysissupporting

confidence: 79%

Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N-acetylephedrine and N-acetylephedrone

et al. 2018

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Purpose Three compounds obtained from ephedrine were identified and characterized by various instrumental analytical methods. Ephedrone (methcathinone) hydrochloride and its fundamental derivatives N-acetylephedrine and N-acetylephedrone were analyzed as precursors of a cathinone derivative. Methods The obtained samples were analyzed by gas chromatography coupled with mass spectrometry, nuclear magnetic resonance spectroscopy, infrared and Raman spectroscopy, and X-ray crystallography. Results The three compounds were confirmed as: N-methyl-2-amino-1-phenylpropan-1-one (methcathinone) hydrochloride, N-acetyl-N-methyl-2-amino-1-phenylpropan-1-one (cathinone derivative), and N-acetyl-N-methyl-2-amino-1-phenylpropan-1-ol (acetyl derivative of ephedrine). Conclusions X-ray crystallography is especially useful for identifying the new designer drugs and their different precursor forms.

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Section: X-ray Analysissupporting

confidence: 79%

Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N-acetylephedrine and N-acetylephedrone

et al. 2018

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“…4 and Table 6). Solution nuclear magnetic resonance spectra of both the free base and the HCl salt are also consistent with this conformation (3,20). Thus, a preferred conformation for mefloquine was established.…”

Section: Discussionsupporting

confidence: 60%

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor

Karle

1991

Antimicrob Agents Chemother

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The crystal structure of (+)-mefloquine methylsulfonate monohydrate was determined by X-ray diffraction and was compared with the crystal structures of mefloquine hydrochloride and mefloquine free base. The conformation of mefloquine was essentially the same in all three crystalline environments and was not dependent on whether mefloquine was a salt or a free base. In mefloquine methylsulfonate monohydrate, the angle between the average plane of the quinoline ring and the average plane of the piperidine ring was 76.90. The intramolecular aliphatic N-13. 0-1 distance was 2.730 ± 0. 3a (F).Since the mechanism of antimalarial action and the mechanism of mefloquine resistance may involve hydrogen bond formation between mefloquine and a cellular effector or transport proteins, the common conformation of mefloquine found in each crystalline environment may define the orientation in which mefloquine forms these potentially critical hydrogen bonds with cellular constituents.The continuing spread of multi-drug-resistant Plasmodium falciparum malaria (22) Understanding the mode of action and mode of resistance of mefloquine on a molecular level should aid the development of new treatment strategies. Although mefloquine alters the pH of the parasite's acid vesicles at nanomolar concentrations (13), the precise mode of action of mefloquine is not well defined. Structure-activity studies demonstrate that mefloquine loses its antimalarial activity if the amine and hydroxyl groups of mefloquine are acetylated (26). Formation of an 0-methyl or O-ethyl derivative as well as conversion of the saturated 2-piperidyl group to an unsaturated 2-pyridyl group also abolishes activity (26). This apparent structural requirement to have underivatized amine and hydroxyl groups suggests that these groups need to be free to hydrogen bond to cellular constituents. Thus, antimalarial activity may depend upon the ability of mefloquine * Corresponding author.to hydrogen bond to a cellular "effector." In addition, structure-activity studies (5, 6, 26) on the 3-and 4-piperidyl isomers of mefloquine and of the 3,6-bis(trifluoromethyl)-9-phenanthryl analog of mefloquine show that the physical placement of the hydroxyl and the amine groups with respect to each other is critical to antimalarial activity. These data further support the hypothesis that these compounds must hydrogen bond to cellular constituents to effect antimalarial activity and must do so with a specific geometry. At present, the mechanism(s) of resistance to mefloquine has not been elucidated (21).The three-dimensional structure of mefloquine defines how the mefloquine molecule physically interacts with a cellular effector or transport proteins. In order to determine the preferred conformation(s) of mefloquine, we undertook the comparison of the structure of mefloquine as both a free base and a salt in three different crystalline environments. The crystal structure of mefloquine methylsulfonate monohydrate (Fig. 1) was determined by X-ray diffraction and was compared with the crysta...

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“…The racemic mixture of mefloquine was provided by the Walter Reed Army Institute for Research. Racemic mefloquine hydrochloride was resolved using the ammonium salt of (ϩ)-3-bromo-8-camphorsulphuric acid to afford (Ϫ)-erythro-mefloquine, as previously described (9). In an analogous fashion, (ϩ)-erythro-mefloquine was obtained using the ammonium salt of (Ϫ)-3-bromo-8-camphorsulphuric acid.…”

Section: Methodsmentioning

confidence: 99%

Identification of (+)-Erythro-Mefloquine as an Active Enantiomer with Greater Efficacy than Mefloquine against Mycobacterium avium Infection in Mice

Bermudez

Inderlied

Kolonoski³

et al. 2012

Antimicrob Agents Chemother

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Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, optical purity, and absolute stereochemistry

Cited by 84 publications

References 5 publications

Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N-acetylephedrine and N-acetylephedrone

Crystal structures and other properties of ephedrone (methcathinone) hydrochloride, N-acetylephedrine and N-acetylephedrone

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor

Identification of (+)-Erythro-Mefloquine as an Active Enantiomer with Greater Efficacy than Mefloquine against Mycobacterium avium Infection in Mice

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