Racemic Mefloquine Research Articles

ChemInform Abstract: A Robust, Recyclable Resin for Decagram Scale Resolution of (.+‐.)‐Mefloquine and Other Chiral N‐Heterocycles.

ChemInformVolume 47, Issue 11 Preparative Organic Chemistry ChemInform Abstract: A Robust, Recyclable Resin for Decagram Scale Resolution of (.+-.)-Mefloquine and Other Chiral N-Heterocycles. Imants Kreituss, Imants Kreituss Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorKuang-Yen Chen, Kuang-Yen Chen Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorSimon H. Eitel, Simon H. Eitel Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorJean-Michel Adam, Jean-Michel Adam Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorGeorg Wuitschik, Georg Wuitschik Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorAlec Fettes, Alec Fettes Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorJeffrey W. Bode, Jeffrey W. Bode Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this author Imants Kreituss, Imants Kreituss Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorKuang-Yen Chen, Kuang-Yen Chen Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorSimon H. Eitel, Simon H. Eitel Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorJean-Michel Adam, Jean-Michel Adam Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorGeorg Wuitschik, Georg Wuitschik Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorAlec Fettes, Alec Fettes Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this authorJeffrey W. Bode, Jeffrey W. Bode Lab. Org. Chem., ETH Zuerich, CH-8093 Zuerich, Switz.Search for more papers by this author First published: 25 February 2016 https://doi.org/10.1002/chin.201611024AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume47, Issue11February, 2016 RelatedInformation

A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles.

Decagram quantities of enantiopure (+)-mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP-gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)-mefloquine and other chiral N-heterocylces.

Differential Effects of Mefloquine Enantiomers on a Cholinergic Synapse

Racemic mefloquine activates spontaneous vesicle release (SVR) from motor nerve endings and inhibits endplate acetylcholinesterase (AChE). Such cholinergic effects may reduce mefloquine's safety as an antimalarial drug. We tested the hypothesis that (+) and (‐) mefloquine differentially affect the neuromuscular junction (NMJ). Intracellular recordings at NMJs of mouse Triangularis sterni muscles suggested that 30 min exposure to 10 μM (+) or (‐) enantiomer alters the frequency of miniature endplate potentials (mEPPs). Quantitative comparisons were not possible since (+) reduced mEPP amplitude. Therefore, we recorded miniature endplate currents (mEPCs). (+) and (‐) significantly (p<0.01) increased mEPC frequency to 59.7 ± 20.05 Sec‐1 (mean ± SEM, N=21 NMJs) and 17.2 ± 1.98 Sec‐1 (N=14), respectively, from the control value of 5.6 ± 0.76 Sec‐1 (N=25). (+) also reduced amplitude (p<0.01) to 2.9 ± 0.18 nAmps (N=21) from the control value of 3.4 ± 0.18 nAmps (N=25); (‐) did not affect mEPC amplitude. (+), but not (‐), significantly (p<0.01) prolonged the endplate current decay time constant to 2.5 ± 0.16 mSec (N=12) from the control value of 1.1 ± 0.05 mSec (N=16). Thus, (+) may reduce conductance and prolong open time of the endplate acetylcholine receptor (AChR) as well as activate SVR. Neither (+) nor (‐) altered stimulus‐evoked quantal release. Assay of whole muscle homogenates revealed that while both enantiomers (1 to 100 μM) inhibit AChE, (‐) is more potent. The data suggest that (‐) is a less potent activator of SVR but a more potent inhibitor of AChE than (+) mefloquine. Supported by the Kirby Foundation.

A randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of single enantiomer (+)-mefloquine compared with racemic mefloquine in healthy persons.

Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (-) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (-)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted.

Schistosomicidal activity of the antimalarial drug, mefloquine, in Schistosoma mansoni-infected mice

Therapeutic effects of racemic mefloquine were assessed in Schistosoma mansoni-infected mice, and evaluated by recording worm burden, the status of egg maturation and viability, and intestinal mast cell recruitment. Age-matched mice were divided into four groups, of which two were infected. At 8 weeks postinfection, one group of infected and one group of uninfected mice were treated with a single dose of mefloquine (150 mg/kg). Ten days after treatment, all animals were killed. Mefloquine at 150 mg/kg had no effect on worm burden, but significantly reduced the number of eggs in the first three developmental egg stages. Analysis of intestinal mast cell numbers showed that mefloquine induced mastocytosis both in infected and control animals. In conclusion, mefloquine significantly reduces egg production in S. mansoni-infected mice, suggesting a therapeutic potency in schistosomiasis therapy. Mefloquine also exerts a significant proinflammatory effect on the intestine. Through its effect on egg production, mefloquine may be a cause of silent schistosomiasis in travelers using mefloquine for malaria chemoprophylaxis. Further study of the anti-schistosomal activity of mefloquine is warranted, as its activity against other helminths.

Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice.

1. Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux protein P-glycoprotein. 2. We investigated the stereoselective uptake and efflux of mefloquine in mice, and the consequences of the combination with an efflux protein inhibitor, elacridar (GF120918) on its brain transport. 3. Racemic mefloquine (25 mg kg(-1)) was administered intraperitoneally with or without elacridar (10 mg kg(-1)). Six to seven mice were killed at each of 11 time-points between 30 min and 168 h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. 4. A three-compartment model with zero-order absorption from the injection site was found to best represent the pharmacokinetics of both enantiomers in blood and brain. (-)Mefloquine had a lower blood and brain apparent volume of distribution and a lower efflux clearance from the brain, resulting in a larger brain/blood ratio compared to (+)mefloquine. Elacridar did not modify blood concentrations or the elimination rate from blood for either enantiomers. However, cerebral AUC(inf) of both enantiomers were increased, with a stronger effect on (+)mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for (+)mefloquine. 5. After administration of racemic mefloquine in mice, blood and brain pharmacokinetics are stereoselective, (+)mefloquine being excreted from brain more rapidly than its antipode, showing that mefloquine is a substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a stereoselective manner. Moreover, pretreatment with elacridar reduced the brain efflux clearances with a more pronounced effect on (+)mefloquine.

Crystal structure of (-)-mefloquine hydrochloride reveals consistency of configuration with biological activity.

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. The crystallographic parameters for (-)-mefloquine hydrochloride hydrate were as follows: C17H17F (6)N(2)O(+)Cl(-) .0.25 H2O; M(r), 419.3; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a = 12.6890 +/- 0.0006 A (1 A = 0.1 nm), b = 18.9720 +/- 0.0009 A, c = 32.189 +/- 0.017 A; volume of unit cell, 7,749 +/- 4 A(3); number of molecules per unit cell, 16; calculated density, 1.44 g cm(-3); source of radiation, Cu Kalpha (lambda = 1.54178 A); mu (absorption coefficient), 2.373 mm(-1); room temperature was used; final R(1) (residual index), 0.0874 for 3,692 reflections with intensities greater than 2sigma. All of the hydroxyl and amine hydrogen atoms participate in intermolecular hydrogen bonds with chloride ions. The orientation of the amine and hydroxyl groups in (+)-mefloquine may define the optimal geometry for hydrogen bonding with cellular constituents.

Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

The brain distribution of the enantiomers of the antimalarial drug mefloquine is stereoselective according to the species. This stereoselectivity may be related to species-specific differences in the properties of some membrane-bound transport proteins, such as P-glycoprotein (P-gp). The interactions of racemic mefloquine and its individual enantiomers with the P-glycoprotein efflux transport system have been analysed in immortalised rat brain capillary endothelial GPNT cells. Parallel studies were carried out for comparison in human colon carcinoma Caco-2 cells. The cellular accumulation of the P-glycoprotein substrate, [ 3H]vinblastine, was significantly increased both in GPNT cells and in Caco-2 cells when treated with racemic mefloquine and the individual enantiomers. In GPNT cells, the (+)-stereoisomer of mefloquine was up to 8-fold more effective than its antipode in increasing cellular accumulation of [ 3H]vinblastine, while in Caco-2 cells, both enantiomers were equally effective. These results suggest that racemic mefloquine and its enantiomers are effective inhibitors of P-gp. Furthermore, a stereoselective P-glycoprotein inhibition is observed in rat cells but not in human cells. The efflux of [ 14C]mefloquine from GPNT cells was decreased when the cells were incubated with the P-gp modulators, verapamil, cyclosporin A or chlorpromazine, suggesting that MQ could be a P-gp substrate.

Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance.

This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers (52% F) participated. AEs with some impact on activities were reported by 11.2% of participants including 7.9% of neurological/psychiatric symptoms. Women were more likely to report AEs (P = 0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic MQ levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability.

Stereoselective Pharmacokinetics of Mefloquine in Healthy Caucasians after Multiple Doses

Mefloquine (MQ) is a chiral antimalarial agent effective against chloroquine‐resistantPlasmodium falciparum.It is commercially available as a racemic mixture of the (+) and (−) enantiomers for oral administration. The pharmacokinetics of the (+) and (−) enantiomers of MQ were studied in eight healthy volunteers after administration of a first oral dose of 250 mg of racemic MQ and at steady state after 13 repeated doses of 250 mg given at 1‐week intervals. Plasma samples were collected, and concentrations of each enantiomer were determined using a previously described achiralchiral double column‐switching liquid chromatographic method. At each time point, higher plasma concentrations values were found for the (−) enantiomer (p< 0.001). At steady state,Cmaxvalues of (−)‐MQ were higher than those of (+)‐MQ (1.42 ± 0.19 versus 0.26 ± 0.05 mg/L;p< 0.001). Similarly, the plasma concentrations 7 days after the final dose were higher for (−)‐MQ (1.01± 0.26 versus 0.11 ± 0.04 mg/L;p< 0.001). AUC values at steady state were also higher for (−)‐MQ (197.3 ± 36.7 versus 30.1 ± 8.9 mg/L·h;p< 0.001). The terminal half‐life values (T1/2β) were longer for (−)‐MQ (430.4 ± 225.2 versus 172.8 ± 56.5 h;p< 0.001). This study shows that the pharmacokinetics of MQ is highly stereoselective.