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  Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.

Schmidt, M., Sun, H., Rogne, P., Scriba, G. K. E., Griesinger, C., Kuhn, L. T., et al. (2012). Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam. Journal of the American Chemical Society, 134(6), 3080-3083. doi:10.1021/ja209050k.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-8449-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-3B0B-1
Genre: Journal Article

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Schmidt, M.1, Author              
Sun, H.1, Author              
Rogne, P., Author
Scriba, G. K. E., Author
Griesinger, C.1, Author              
Kuhn, L. T., Author
Reinscheid, U. M.1, Author              
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1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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 Abstract: Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (−) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived 3JHH scalar couplings, 15N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (−)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (−)-erythro-mefloquine HCl is correct.

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Language(s): eng - English
 Dates: 2011-12-072012-02-15
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/ja209050k
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Title: Journal of the American Chemical Society
Source Genre: Journal
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Pages: - Volume / Issue: 134 (6) Sequence Number: - Start / End Page: 3080 - 3083 Identifier: -