Antimalarial activity and conformation of erythro- and threo-.alpha.-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol

Olsen, Robert E.

doi:10.1021/jm00272a024

Cited by 12 publications

(8 citation statements)

References 5 publications

(5 reference statements)

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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: 58%

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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Section: Discussionsupporting

confidence: 58%

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

Karle

1991

Antimicrob Agents Chemother

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“…It is not known which is the active racemate of 2. The racemate of the 4-piperidyl compound (3), which has only one chiral center, is inactive.2 NMR studies3 of compound 1 suggest a preferred conformation in solution where the rotation of the piperidyl ring leads to a staggered configuration with the quaternary nitrogen atom directed away from the phenanthrene ring. Evidence4 involving the correlation of activity with the basicity of the nitrogen atom suggests5 that the protonated form of the nitrogen is active.…”

mentioning

confidence: 99%

Conformational studies of a family of related antimalarial phenanthrene amino alcohols

Loew¹,

Sahakian²

1977

J. Med. Chem.

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A conformational study utilizing quantum chemical methods was performed on a family of antimalarial alpha-(piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanols whose structures differ by the placement of the substituent on either the 2,3, or 4 position of the piperidyl ring. The antimalarial activity of these 3-substituted compounds has been shown experimentally to be highly stereospecific while the 2-substituted compounds are not and the 4-substituted compounds are inactive. In this study, such observed differences in behavior are correlated with conformational results and a pharmacophore is postulated. The identity of the active racemate of the 3-piperidyl compound is predicted.

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“…In this current Army research program on malaria, a large number of phenanthrene-, quinoline-, and pyridinearylcarbinolamines of type 1 and 2 were prepared for antimalarial screening. As a part of this program, Nodiff and coworkers3 prepared one racemate (3a) of a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9phenanthrenemethanol (3) and Olsen4 isolated the other racemate (3b).t Both of the compounds were found to be very active against resistant strains of both P. berghei in rodents and P. falciparum in Aotus monkeys.t In addition, both the major and minor racemates of a-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol (4) have been prepared by Lutz and coworkers® and Olsen, Í respectively, and shown to be highly active against P. berghei in mice and P. falciparum in Aotus monkeys.! 3 4 In this paper we report the preparation of all four optical isomers of both 3 and 4, describe methods for establishing their optical purity, and discuss procedures for establishing both the relative and absolute configuration of these compounds.…”

mentioning

confidence: 99%

“…Figure4. Nmr spectra of (A) 20 mg of (±)-N-acetyl-a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol ((±)-6a], (B) 20 mg of (-) -JV-acetyl-a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol [(-)-6a], and (C) 20 mg of (+)-N-acetyl-a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol [(+)-6a], respectively, in 0.3 ml of CCU containing 10 mg of tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III) in case A and 14 mg in case B and C.…”

mentioning

confidence: 99%

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

Carroll¹,

Blackwell²

1974

J. Med. Chem.

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Antimalarial activity and conformation of erythro- and threo-.alpha.-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanol

Cited by 12 publications

References 5 publications

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

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

Conformational studies of a family of related antimalarial phenanthrene amino alcohols

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

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