Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Abstract

The absolute configuration of (؊)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquine's optical isomers to those of quinine and quinidine. (؊)-Mefloquine has the same stereochemistry as quinine, and (؉)-mefloquine has the same stereochemistry as quinidine. Since (؉)-mefloquine is more potent than (؊)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (؊)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. Quinine and quinidine (Fig. 1), antimalarial agents isolated from the bark of the Cinchona tree, are diastereomers, but they mirror each other at carbons C-8 and C-9. In vitro quinidine is more potent than quinine against many strains of Plasmodium falciparum. Specifically, quinidine is 2.3 and 2.8 times more potent than quinine against the chloroquine-sensitive Sierra Leone D-6 clone and the chloroquine-resistant Indochina W-2 clone, respectively (15). Quinidine is 2.5 times more potent than quinine and cinchonine (the demethoxy analog of quinidine) is 2.8 times more potent than cinchonidine (the demethoxy analog of quinine) in vitro against Papua New Guinea FCQ-27/PNG P. falciparum (25). Similarly, quinidine was 2.2 and 3.2 times more potent than quinine against Cameroon chloroquine-resistant FCM 29 and Ivory Coast chloroquine-sensitive L-3 strains, respectively (1). Against clinical isolates from Liberia, quinidine was on average 3 times more potent than quinine (4). Clinical differences in the antimalarial activities of quinine and quinidine have also been reported. Compared to quinine, quinidine was twice as effective against induced McClendon P. falciparum infections (23) and more potent clinically against Thai P. falciparum (18,26).Mefloquine, a synthetic analog of quinine and quinidine, is marketed in racemic form under the trade name Lariam. Mefloquine is basically a structurally simpler form of quinine and quinidine. Mefloquine differs from the cinchona alkaloids in that it has a different substitution on the quinoline ring, a piperidine ring rather than the bicyclo quinuclidine ring, and no vinyl group (see Fig. 1). However, the C-8 and C-9 chiral centers of the cinchona alkaloids are preserved in the mefloquine molecule (numbered C-12 and C-11, respectively). Thus, one enantiomer of mefloquine will share the same stereochemistry as quinine and the other enantiomer of mefloquine will share the same stereochemistry as quinidine at the equivalent chiral centers.Since quinine and quinidine possess different antimalarial activities, the (ϩ) and (Ϫ) isomers of mefloquine were tested against P. falc...

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

“…It is of note that, in contrast to threo CA, the racemate of 12, 11 threo MQ is as potent as the racemate of 12, 11 erythro mefloquine against Plasmodium berghei and P. falciparum in vitro (38,67). This difference reflects the increased ease of rotation around the link between the asymmetric carbon atoms due to the lower bulk of the piperidine ring as opposed to that of quinuclidine (36,67). The bulkier quinuclidine side chain of the CA may contribute to a loss of flexibility, imparting a structural constraint that may confer the greater stereospecificity of the CA than the other quinolines (19).…”

“…1), also possess differential activities against P. falciparum. The (ϩ)-isomer of MQ, shown to be the stereo-equivalent of QD in terms of absolute conformation, reportedly has 1.7 to 1.8 times greater activity than (Ϫ)-MQ, the QN equivalent (36,38). We tested 106/1, 106/1 76I , and 106/1 76I-369F (Table 3) in drug assays to determine if the unusual effects of these PfCRT mutations on the CA was extended to the structurally similar MQ isomers.…”

“…The steric and electronic features of the CA that contribute to the potency of the erythro conformations are believed to impart an enhanced ability to form intramolecular hydrogen bonds with a plasmodial receptor(s) (18,35,36). Although the presence of such a target molecule serving as a stereoselective receptor appears evident in the action of the CA, the nature of this receptor has yet to be determined.…”

Determining the Absolute Configuration of (+)-Mefloquine HCl, the Side-Effect-Reducing Enantiomer of the Antimalaria Drug Lariam

“…5 This first assignment was rejected and inverted by anomalous X-ray diffraction in 2002. 6 In 2008, however, a total synthesis using a proline-catalyzed asymmetric direct aldol reaction (recently reviewed for its broad applicability 7 ) and Beckmann rearrangement followed by a Mosher analysis 8 reconfirmed the original assignment. 9 Because these established methods for the determination of the absolute configuration, namely, anomalous diffraction and stereoselective synthesis, gave contrary results, we determined the absolute configuration using residual dipolar coupling (RDC)-enhanced NMR spectroscopy in combination with optical rotatory dispersion (ORD) and CD spectroscopy.…”

“…The planar quinoline fragment and the piperidine ring, in a chair conformation with an equatorial alkyl substituent at C12, are rigid, 6 For the three torsion angles τ 1 , τ 2 , and τ 3 , the ROE spectroscopy (ROESY) cross-peaks (Scheme 1) indicated that there are preferred conformations that clearly distinguish between the two sides of the quinoline fragment relative to the substituent at C4: on the one hand, the strong ROEs between 5 and 11 and between 5 and 12ax, and on the other hand, the missing ROEs between 5 and 17eq and between 5 and 17ax (eq = equatorial, ax = axial). Additionally, the 3 J H11H12 = 2.7 Hz coupling and two strong 3 J HC heteronuclear multiplebond correlation (HMBC) signals ( 3 J H11C17 and 3 J H11C3 ) indicated preferred values of τ 1 and τ 2 .…”