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Tafenoquine

Synopsis, Chemistry

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Also known as: 106635-80-7, Etaquine, Arakoda, Krintafel, Wr 238605, Sb-252263-aab

Molecular Formula

C₂₄H₂₈F₃N₃O₃

Molecular Weight

463.5 g/mol

InChI Key

LBHLFPGPEGDCJG-UHFFFAOYSA-N

FDA UNII

262P8GS9L9

Tafenoquine is an orally bioavailable 8-aminoquinoline derivative, with antimalarial activity. Although the mechanism is not completely understood, upon administration, tafenoquine inhibits the parasitic enzyme heme polymerase in the blood stages of the parasites. This inhibits the conversion of the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. Tafenoquine is active against all the stages of Plasmodium species and is also active against the pre-erythrocytic liver stages of the parasites. This prevents the development of the erythrocytic forms of the parasite which are responsible for relapses in P. vivax malaria.

1 2D Structure

Tafenoquine

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine

2.1.2 InChI

InChI=1S/C24H28F3N3O3/c1-14-11-20(32-4)30-22-18(29-15(2)7-6-10-28)13-19(31-3)23(21(14)22)33-17-9-5-8-16(12-17)24(25,26)27/h5,8-9,11-13,15,29H,6-7,10,28H2,1-4H3

2.1.3 InChI Key

LBHLFPGPEGDCJG-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=CC(=NC2=C1C(=C(C=C2NC(C)CCCN)OC)OC3=CC=CC(=C3)C(F)(F)F)OC

2.2 Other Identifiers

2.2.1 UNII

262P8GS9L9

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (r)-tafenoquine Succinate

2. Arakoda

3. Butanedioic Acid, Compd. With N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine (1:1)

4. Butanedioic Acid, Compd. With N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine (1:1), (r)-

5. Krintafel

6. N(4)-(2,6-dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine

7. Sb-252263-ax

8. Sb-252263ax

9. Sb252263-ax

10. Sb252263ax

11. Tafenoquine Maleate

12. Tafenoquine Succinate

13. Tafenoquine Succinate, (r)-

14. Wr 238605

15. Wr-238605

16. Wr238605

2.3.2 Depositor-Supplied Synonyms

1. 106635-80-7

2. Etaquine

3. Arakoda

4. Krintafel

5. Wr 238605

6. Sb-252263-aab

7. Tafenoquine Free Base

8. Wr238605

9. 262p8gs9l9

10. 106635-80-7 (free Base)

11. 4-n-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine

12. Tafenoquine (usan)

13. Tafenoquine [usan]

14. N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-yl)pentane-1,4-diamine

15. 1,4-pentanediamine, N4-(2,6-dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-8-quinolinyl)-

16. Sb-252263

17. Unii-262p8gs9l9

18. Tafenoquine [usan:inn:ban]

19. 1,4-pentanediamine, N4-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-

20. N(4)-(2,6-dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine

21. Tafenoquine [mi]

22. Tafenoquine [inn]

23. (r)-n3-(2,6-dimethoxy-4-methyl-5-(3-trifluoromethyl)phenoxy)quinolin-8-yl)pentane-1,4-diamine

24. Tafenoquine [mart.]

25. Tafenoquine [who-dd]

26. Schembl347388

27. Chembl298470

28. Gtpl9722

29. Dtxsid90869466

30. Chebi:141487

31. Ex-a3146

32. Db06608

33. Sb16555

34. (rs)-n(sup 3)-(2,6-dimethoxy-4-methyl-5-(3-trifluoro-methylphenoxy)quinolin-8-yl)pentane-1,4-diamine

35. Hy-111529

36. Cs-0042381

37. Ft-0775258

38. D10490

39. D87160

40. Q2387553

41. N4-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolyl]pentane-1,4-diamine

42. (+/-)-8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy) Quinoline

43. (4-amino-1-methylbutyl){2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy](8-quinolyl)}amine

44. N(4)-{2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine

2.4 Create Date

2005-08-01

3 Chemical and Physical Properties

Molecular Formula	C₂₄H₂₈F₃N₃O₃
Molecular Weight	463.5 g/mol
XLogP3	5.4
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	9
Exact Mass	463.20827625 g/mol
Monoisotopic Mass	463.20827625 g/mol
Topological Polar Surface Area	78.6 Å²
Heavy Atom Count	33
Formal Charge	0
Complexity	597
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	1
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria. Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by _Plasmodium vivax_, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses.

FDA Label

5 Pharmacology and Biochemistry

5.1 Pharmacology

In vitro studies have shown that tafenoquine presents an average 50% inhibitory concentration of 0.436 mcg against blood stages of seven strains of _P. falciparum_. In chloroquine-resistant _P. falciparum_ strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0.5 to 33.1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of _P. vivax_, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91.9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99.1% against vivax malaria.

5.2 MeSH Pharmacological Classification

Antimalarials

Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)

5.3 ATC Code

P - Antiparasitic products, insecticides and repellents

P01 - Antiprotozoals

P01B - Antimalarials

P01BA - Aminoquinolines

P01BA07 - Tafenoquine

5.4 Absorption, Distribution and Excretion

Absorption

The first-in-human pharmacokinetic study showed a tmax of 13.8 hours and this study suggested that the prolonged absorption from the gut can be due to absorption in the distal gastrointestinal tract combined with a slow clearance. The AUC and Cmax demonstrated an intersubject variability. The bioavailability of tafenoquine is increased in the presence of a high-fat meal by modifying the amount of drug absorbed rather than the rate of absorption. Once absorbed, the concentration of tafenoquine in the whole body is two-fold higher than the corresponding concentration in plasma and it seems to be highly distributed in the liver showing an AUC of approximately 80 times more than what is found in the plasma.

Route of Elimination

After degradation by different metabolic pathways, tafenoquine is slowly excreted from the body primarily in the feces and renal elimination of the unchanged form is very low.

Volume of Distribution

Tafenoquine presents a high volume of distribution of approximately 2 560 L.

Clearance

Tafenoquine presents a low clearance of approximately 6 L/h.

5.5 Metabolism/Metabolites

The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain.

5.6 Biological Half-Life

Tafenoquine presents a long half-life of approximately 14 days.

5.7 Mechanism of Action

The mechanism of action of tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by _P. falciparum_ which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites.