title: Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.
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 (3)J(HH) scalar couplings, (15)N 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.
authors.affiliation: Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schmidt
authors.forename: Han
authors.initials: H
authors.lastname: Sun
authors.forename: Per
authors.initials: P
authors.lastname: Rogne
authors.forename: Gerhard K E
authors.initials: GK
authors.lastname: Scriba
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Lars T
authors.initials: LT
authors.lastname: Kuhn
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Reinscheid
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D006851:Hydrochloric Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015767:Mefloquine / Q000737:chemistry* / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009905:Optical Rotatory Dispersion / Q000379:methods; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D000962:Antimalarials; D018047:Receptors, Purinergic P1; D006851:Hydrochloric Acid; D015767:Mefloquine