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

Abstract

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...

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

“…The crystalline conformations of (Ϫ)-mefloquine hydrochloride are virtually identical to the crystalline conformations of racemic mefloquine with regard to their hydrochloride salts (13), methylsulfonate salts (14), and free bases (17). Table 3 shows that the distances between the aliphatic nitrogen atom and hydroxyl oxygen atom, the positions of the hydroxyl and amine groups, and the positions of the quinoline and piperidine rings are essentially identical for all of the mefloquine molecules.…”

“…The implication from studies of the stereochemistry and stereospecificity of antimalarial potency of mefloquine and the cinchona alkaloids is that these compounds have a common malaria receptor (14). In Fig.…”

Synthesis, characterization and crystal structures of the tetrachlorocuprate and tetrabromocadmate salts of the antimalarial mefloquine

“…5). Bond lengths and angles for the mefloquine cation in both structures are within the ranges reported previously [17,18,28]. The mefloquine molecule is protonated at the piperidinyl N atom, resulting in a significant lengthening of the N22-C bonds by *0.02-0.03 Å when compared to these bonds in mefloquine freebase [18].…”

“…This and -54.5(6)°-[-66.6(3)°] for the latter. In addition, torsion angles H20-O20ÁÁÁN22-H22A and H20-O20ÁÁÁN22-H22B in compounds 1 and 2, defining hydrogen bond directions, fall within the range of analogous parameters for mefloquine methyl sulfonate monohydrate and mefloquine hydrochloride, namely -14.6°to -18.1°and 82.6°to 93.0° [17]. Selected hydrogen bonds occurring in compounds 1 and 2 are depicted in Figs.…”

“…The biological relevance of such salts was highlighted in a report on the crystal structure of mefloquine methylsulfonate monohydrate [17] and, very recently, in a comparison of the structures of mefloquine free base and its hydrochloride and tetrachlorocobaltate salts [18].…”