Further side-chain modification of antimalarial phenanthrene amino alcohols

Chien, Ping-Lu; Cheng, C. C.

doi:10.1021/jm00268a006

Cited by 13 publications

(4 citation statements)

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“…These confor----a~~~~~~F IG. 5 mations may define the geometry of hydrogen bond formation between a receptor and amino alcohol antimalarial compounds.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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“…These confor----a~~~~~~F IG. 5 mations may define the geometry of hydrogen bond formation between a receptor and amino alcohol antimalarial compounds.…”

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Es war geplant, MeOH an 1 zu addieren und das a-Methoxyamid 2 (X = OCH 3 ) in Gegenwart von Lewissäuren mit Nucleophilen, wie Silylenolethern. umzusetzen.…”

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Asymmetrische α‐Amidoalkylierung: Synthesen enantiomerenreiner α‐substituierter Piperidine mit 1‐Camphanoyl‐1,2,3,4‐tetrahydropyridin

Wanner

Kärtner

1987

Archiv der Pharmazie

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Ph 330[In einer neuartigen. asymmetrischen Synthese wird das homochirale Enamid I diastereoselektiv mit den Silylenolethern 5a-e zu den Amidoalkylierungsprodukte 6/7a-e verknüpft, die für die Gewinnung enantiomerenreiner in a-Stellung R-und S-konfigurierter Piperidinalkohole 9, des Piperidinketons 13, der (R)-Homopipecolinsäure 12R und des Alkaloids (+ )-Sedamin IORR eingesetzt werden.Asymmetrie a-Amidoalkylation. Syntheses ofEnantiomerieally Pure a-Substituted Piperidines with I-Camphanoyl-I,2,3,4-tetrahydropyridine In a novel asymmetrie synthesis the homoehiral enamide I is coupled with the silyl enol ethers 5a-e in a diastercoselectivc fashion to afford the amidoalkylation produets 6/7a-e. These are employed in the synthesis of enantiomerically pure, in a-position Rand S-eonfigurated piperidine alcohols 9, the piperidine ketone 13, (R)-homopipccolie acid 12R and the alkaloid (+ )-sedamine IORR.2-Piperidylethanol ist als Strukturelement in Substanzen mit pharmakologischen Wirkungen weit verbreitet und kommt z. B. in dem Blutplättchenaggregationshemmer 2 ) Ia, dem AntimalariamitteP) Ib und dem ausführlich untersuchten Analgetikum II4) vor. Auch in Naturstoffen wie (-)-Sedamin (IIIa)5) aus Sedum acre und (+ )-Norallosedamin 6a ) (IIIb) aus Lobelia iriflata ist es anzutreffen.

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“…13 At the time our work began it was already apparent that a nitrogen-containing ring structure was not a necessary feature for high antimalarial activity; the phenanthrenemethanols were known to be among the most active antimalarials. [14][15] Chemistry. The synthesis routes to the compounds listed in Table I involved conversion of the carboxyl group in the appropriate fluoreneor fluorenenonecarboxylic acid to the desired di-n-butylaminomethylmethanol side chain by the procedure used previously.…”

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confidence: 99%