mefloquine   

GtoPdb Ligand ID: 4252

Synonyms: GNF-Pf-5544 | Lariam® | Ro-21-5998-001 | WR-142490
mefloquine is an approved drug (FDA (1989), UK (1989))
Compound class: Synthetic organic
Comment: Mefloquine belongs to the aryl amino alcohols, a chemical class of antimalarial drugs that includes quinine, lumefantrine and halofantrine.
The approved drug is a racemic mixture of (R,S)- and (S,R)-enantiomers. We show the chemical structure without stereochemistry to represent the mixture and the non-isomeric structure is also represented in the PubChem and ChEMBL entries listed in the links table below, while the two enantiomers forming the racemate are represented by PubChem CID 40692 and PubChem CID 456309. PubChem lists 9 stereoisotopes.
The administerd form contains the mefloquine hydrochloride salt.

The Malaria tab on this ligand page provides additional curator comments of relevance to the Guide to MALARIA PHARMACOLOGY.

Activity at non-malarial protein targets:
Racemic mefloquine has been identified as an antagonist of the human adenosine A2A and A1 receptors, with nanomolar binding affinities [8]. The (11R,2'S) isomer of mefloquine (PubChem CID 456309) has been determined as the most potent A2A binder, with a Ki of 61 nM (Ki vs. A1 receptor is 255 nM) [4]. It has been suggested that off-target activity at human adenosine receptors may contribute towards the adverse neuropsychiatric side-effects that are associated with mefloquine use.
2D Structure
Click here for structure editor
Physico-chemical Properties
Hydrogen bond acceptors 3
Hydrogen bond donors 2
Rotatable bonds 4
Topological polar surface area 45.15
Molecular weight 378.12
XLogP 3.87
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES OC(c1cc(nc2c1cccc2C(F)(F)F)C(F)(F)F)C1CCCCN1
Isomeric SMILES OC(c1cc(nc2c1cccc2C(F)(F)F)C(F)(F)F)C1CCCCN1
InChI InChI=1S/C17H16F6N2O/c18-16(19,20)11-5-3-4-9-10(15(26)12-6-1-2-7-24-12)8-13(17(21,22)23)25-14(9)11/h3-5,8,12,15,24,26H,1-2,6-7H2
InChI Key XEEQGYMUWCZPDN-UHFFFAOYSA-N
References
1. Brasseur P, Kouamouo J, Brandicourt O, Moyou-Somo R, Druilhe P. (1988)
Patterns of in vitro resistance to chloroquine, quinine, and mefloquine of Plasmodium falciparum in Cameroon, 1985-1986.
Am. J. Trop. Med. Hyg., 39 (2): 166-72. [PMID:3044155]
2. Delves M, Plouffe D, Scheurer C, Meister S, Wittlin S, Winzeler EA, Sinden RE, Leroy D. (2012)
The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites.
PLoS Med., 9 (2): e1001169. [PMID:22363211]
3. Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, Prabhu N, Sobota RM, Bozdech Z, Nordlund P. (2019)
Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay.
Sci Transl Med, 11 (473). [PMID:30602534]
4. Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, Dourish CT, Fletcher A, Gaur S, Giles PR et al.. (2008)
Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives.
Bioorg. Med. Chem. Lett., 18 (9): 2916-9. [PMID:18406614]
5. Karbwang J, White NJ. (1990)
Clinical pharmacokinetics of mefloquine.
Clin Pharmacokinet, 19 (4): 264-79. [PMID:2208897]
6. Sheridan CM, Garcia VE, Ahyong V, DeRisi JL. (2018)
The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved anti-malarials.
Malar. J., 17 (1): 465. [PMID:30541569]
7. Trenholme CM, Williams RL, Desjardins RE, Frischer H, Carson PE, Rieckmann KH, Canfield CJ. (1975)
Mefloquine (WR 142,490) in the treatment of human malaria.
Science, 190 (4216): 792-4. [PMID:1105787]
8. Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, Misra A, Pratt RM, Revell D, Upton R et al.. (2003)
Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease.
Neurology, 61 (11 Suppl 6): S101-6. [PMID:14663021]
9. Wong W, Bai XC, Sleebs BE, Triglia T, Brown A, Thompson JK, Jackson KE, Hanssen E, Marapana DS, Fernandez IS et al.. (2017)
Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis.
Nat Microbiol, 2: 17031. [PMID:28288098]
10. (2015)
Treatment of uncomplicated Plasmodium falciparum malaria.  In  Guidelines for the Treatment of Malaria. Third edition. (World Health Organization) . [PMID:26020088] [ISBN:9789241549127]