The molecular and crystal structure of the alkaloid cinchonine

Oleksyn, Barbara J.; Lebioda,; Ciechanowicz-Rutkowska, M.

doi:10.1107/s0567740879003721

Cited by 52 publications

(55 citation statements)

References 2 publications

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“…The bond lengths and angles in the bicyclic quinuclidine part of the molecule agree well with those observed in other Cinchona alkaloids such as derivatives of quinine and quinidine (Suszko-Purzycka et al, 1985;Suszko-Purzycka, Lipifiska, Karczmarzyk & Pniewska, 1987;Dupont et al, 1985), quinidine (Kashino & Haisa, 1983), cinchonidine (Oleksyn, 1982) and cinchonine (Oleksyn et al, 1979). However, the asymmetry of the N(1) -C(8) (41) 0.8022 (6) 0.500 0.500 11.4 (2) C (42) 0.7300 (5) 0.5122 (2) 0.5459 (2) 11.7 (1) C (43) 0.6025 (4) 0.5115 (2) 0.5447 (1) 7.9 (1) C (44) 0.5399 (5) 0.500 0.500 7.0 (1) C (45) 0.3935 (7) 0.500 0.500 14.1 (3) C (6) …”

Section: Meosupporting

confidence: 69%

“…quinidine (Kashino & Haisa, 1983), cinchonidine (Oleksyn, 1982) and cinchonine (Oleksyn, Lebioda & Ciechanowicz-Rutkowska, 1979), it was impossible to obtain quinine in pure form by simple recrystallization of the commercial product. Commercial preparations of quinine, obtained from cinchona bark, contain small amounts of other alkaloids, among them dihydroquinine (Henry, 1949;Suszko-Purzycka & Trzebny, 1964, 1965.…”

mentioning

confidence: 99%

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Structure of quinine monohydrate toluene solvate

Pniewska¹,

Suszko-Purzycka²

1989

Acta Crystallogr C

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Section: Meosupporting

confidence: 69%

mentioning

confidence: 99%

Structure of quinine monohydrate toluene solvate

Pniewska¹,

Suszko-Purzycka²

1989

Acta Crystallogr C

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“…4 that all four mefloquine molecules share nearly the same conformation. (1,4,7,9,12,(14)(15)(16)(17)23). For all four mefloquine molecules, the C-4-C-11-C-12-N-13 torsion angle was close to 1800, placing N-13 about as far away from the quinoline ring as possible.…”

Section: Coordinates and Thermal Parameters (Ueq Values) (Seementioning

confidence: 99%

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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“…Interproton distances for calculations of relaxation pathways were obtained from crystal structure coordinates of cinchonine (12), quinidine (131, morphine (l5), codeine ( l6), and heroin (1 7), and from Dreiding molecular models. For calculating the relaxation contributions from methoxyl groups to adjacent ring protons, it was necessary to examine results from a number of models for methoxy conformation and dynamics.…”

Section: Methodsmentioning

confidence: 99%