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Tafenoquine: a 2018 Novel FDA-Approved Prodrug for the Radical Cure of Plasmodium Vivax Malaria and Prophylaxis of Malaria

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Tafenoquine: a 2018 Novel FDA-Approved Prodrug for the Radical Cure of Plasmodium Vivax Malaria and Prophylaxis of Malaria pharmaceuticals Brief Report Tafenoquine: A 2018 Novel FDA-Approved Prodrug for the Radical Cure of Plasmodium vivax Malaria and Prophylaxis of Malaria Annie Mayence 1 and Jean Jacques Vanden Eynde 2,* 1 Haute Ecole Provinciale de Hainaut-Condorcet, 7330 Saint-Ghislain, Belgium 2 Formerly head of the Department of Organic Chemistry (FS), University of Mons-UMONS, 7000 Mons, Belgium * Correspondence: [email protected] Received: 16 July 2019; Accepted: 27 July 2019; Published: 30 July 2019 Abstract: Tafenoquine (an 8-aminoquinoline) was approved by the Food and Drug Administration (FDA) in 2018 for the radical cure of Plasmodium vivax malaria and preventive action against malaria. Despite the fact that the mechanism of action of the drug remains unclear, all studies indicated that a metabolite is responsible for its efficacy. Routes for the preparation of the drug are described. Keywords: aminoquinoline; approved drugs; FDA; hypnozoite; malaria; Plasmodium 1. Introduction Despite many campaigns of prevention and vaccination, malaria remains a major cause of deceases in developing countries. Following the World Malaria Report 2018 [1], published by the World Health Organization (WHO), the disease still affected 219 million people and killed 435,000 patients in 2017. The infection is caused by protozoans named Plasmodium, whose life cycle has been elegantly illustrated by Campo et al. [2] Five species are responsible for the human disease: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Chloroquine (1, Figure1), a 4-aminoquinoline, still constitutes a common, cheap, and safe drug for the treatment of malaria caused by any type of Plasmodium. However, its intensive use has led to the emergence of resistant strains of parasites. Actually, it is recommended to fight those resistant strains by administration of two drugs with different modes of action. Currently, Artemisinin-based Combination Therapy (ACT) is the most popular treatment [3]. It is worth noting that, contrary to the other species of Plasmodium, P. vivax and P. ovale produce hypnozoites during their life cycle in the liver. They are latent forms of the parasite, which are able to reactivate the illness, a relapse, without any bite of an infected mosquito. Primaquine (2, Figure1; Primacin™), an 8-aminoquinoline, is the drug of choice to eradicate hypnozoites and is often used in conjunction with other anti-Plasmodium agents (schizontocides) in the radical cure of vivax malaria [2–4]. Tafenoquine (3, Figure1), another 8-aminoquinoline, was discovered by the Walter Reed Army Institute of Research (WR238605) in 1978. After numerous in vitro and in vivo studies, it has been shown to be superior to primaquine as a novel anti-malarial agent. More details on tafenoquine are given below. Pharmaceuticals 2019, 12, 115; doi:10.3390/ph12030115 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2019, 12, 115 2 of 7 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 2 of 8 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 2 of 8 FigureFigure 1. Structure1. Structure ofof aminoquinolines (1–3 ()1. –3). 2. Tafenoquine 2. Tafenoquine 2.1. Names2.1. Names The InternationalThe International Union Union of Figureof PurePure 1. andStructure and Applied Applied of aminoquinolines Chemistry Chemistry (IUPAC (1–3). ) (IUPAC)name of tafenoquine name of is tafenoquine4-N- is 4-N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine,[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine, CAS 2. Tafenoquine CAS 106635-80-7.106635-80-7. Tafenoquine (3) is commercialized, as the succinate salt (CAS 106635-81-8) of racemate, under 2.1. Names Tafenoquinethe names Krintafel (3) is commercialized, ™ [5] (tablets of 150 as mg) the by succinate GlaxoSmithKline salt (CAS (GSK, 106635-81-8) Brentford, Middlesex, of racemate, UK) under the namesas KrintafelwellThe as International Arakoda™ [5] ™ (tablets Union [6] and of of Kodatef®Pure 150 and mg) Applied(tablets by GlaxoSmithKline ofChemistry 100 mg) (byIUPAC 60 Degrees (GSK,) name of Brentford,Pharmaceuticals tafenoquine Middlesex, is 4LLC-N- UK) as well as[2,6(WashingtonArakoda-dimethoxy DC,™-4- methyl[USA)6] and. -5-[3 Kodatef-(trifluoromethyl)phenoxy]quinolin® (tablets of 100 mg)- by8-yl]pentane 60 Degrees-1,4-diamine Pharmaceuticals, CAS LLC (Washington,106635 DC,-80-7. USA). 2.2. UsesTafenoquine (3) is commercialized, as the succinate salt (CAS 106635-81-8) of racemate, under 2.2. Usesthe namesTafenoquine Krintafel was ™ approved[5] (tablets by of the150 USmg) Food by GlaxoSmithKline and Drug Administration (GSK, Brentford, (FDA) onMiddlesex, July 20, 2018UK), asfor well radical as Arakodacure of Plasmodium ™ [6] and vivaxKodatef® malaria (tablets (Krintafel™) of 100 mg), that by indication 60 Degrees is part Pharmaceuticals of the portfolio LLC of Tafenoquine(WashingtonGSK. The drug was DC, is approvedalsoUSA) prescribed. by for the the US prophylax Food andis of malaria Drug. Administration That aspect is handled (FDA) by 60 on Degrees 20 July 2018, for radicalPharmaceuticals cure of Plasmodium LLC. vivax malaria (Krintafel™), that indication is part of the portfolio of 2.2. Uses GSK. The drug is also prescribed for the prophylaxis of malaria. That aspect is handled by 60 Degrees 2.3. Mechanisms of Action PharmaceuticalsTafenoquine LLC. was approved by the US Food and Drug Administration (FDA) on July 20, 2018, for radicalThere cureremain of Plasmodiumsome uncertainties vivax malaria concerning (Krintafel™) the mechanism, that indication of action is of part 8-aminoquinolines of the portfolio ofin 2.3. MechanismsGSKgeneral. The and ofdrug Actiontafenoquine is also prescribed in particular. for the T prophylaxhe radical cureis of malariaactivity. of That primaquine aspect is handled(2) and tafenoquine by 60 Degrees (3) Pharmaceuticalsis thought to be relatedLLC. to the 5,6-quinone species 4 (Figure 2), one of the numerous metabolites [7] Thereproduced remain through some degradation uncertainties by cytochrome concerning P450 the 2D6 mechanism liver microsomal of action enzyme. of That 8-aminoquinolines hypothesis in general and2.3.was Mechanisms tafenoquinefounded on of inAction invitro particular. [8] and in Thevivo radical[9] studies. cure In activityaddition, ofthe primaquine ortho-quinone ( 24) was and detected tafenoquine (3) is thoughtduring toThere be a relatedpharmacokinetic remain tosome the uncertainties 5,6-quinone analysis performed concerning species from the4 (Figure animalsmechanism 2that), oneof had action of received the of 8 numerous-aminoquinolines 8-aminoquinolines metabolites in [ 7] [10]. The same quinone (4) could be responsible for adverse effects (hemolytic anemia) in patients producedgeneral through and tafenoquine degradation in particular. by cytochrome The radical P450 cure 2D6 activity liver of microsomalprimaquine (2)enzyme. and tafenoquine That hypothesis(3) iswith thought glucose to be-6- phosphaterelated to the dehydrogenase 5,6-quinone species (G6PD) 4 (Figuredeficiency, 2), one leading of the tonumerous a contraindication metabolites [7]for was foundedproducedpregnant on womenthroughin vitro [ 2degradation,11[8]. and in by vivo cytochrome[9] studies. P450 2D6 In liver addition, microsomal the orthoenzyme.-quinone That hypothesis4 was detected during awas pharmacokinetic founded on in vitro analysis [8] and performed in vivo [9] studies. from animals In addition, that the had ortho received-quinone 8-aminoquinolines 4 was detected [10]. The sameduring quinone a pharmacokinetic (4) could be analysis responsible performed for adversefrom animals effects that (hemolytichad received anemia)8-aminoquinolines in patients with glucose-6-phosphate[10]. The same quinone dehydrogenase (4) could be (G6PD) responsible deficiency, for adverse leading effects (hemolytic to a contraindication anemia) in patients for pregnant women [with2,11 ].glucose-6-phosphate dehydrogenase (G6PD) deficiency, leading to a contraindication for pregnant women [2,11]. Figure 2. Key metabolite (4) of 8-aminoquinolines 2 and 3. Interestingly, the presence of the aryl ether in position 5 of tafenoquine 3 decreases the susceptibility of oxidation required to yield 4 [2]. Not surprisingly, an elimination half-life of 14 days FigureFigure 2. Key 2. Key metabolite metabolite ((4) of 8 8-aminoquinolines-aminoquinolines 2 and2 3and. 3. Interestingly,Interestingly, the presence the presence of the arylof the ether aryl inether position in position 5 of tafenoquine 5 of tafenoquine3 decreases 3 decrease thes susceptibility the of oxidationsusceptibility required of oxidation to yield required4 [2]. Notto yield surprisingly, 4 [2]. Not surprisingly, an elimination an elimination half-life half- oflife 14 of 14 days days has been observed for tafenoquine 3 against a few hours for primaquine 2 [12]. Consequently, comparable anti-plasmodial efficacy can be attained in humans with a single dose only of 300 mg of 3, whereas primaquine (2) must be administered daily (15 mg) for two weeks [2]. Pharmaceuticals 2019, 12, 115 3 of 7 Pharmaceuticals 2019, 12, x FOR PEER REVIEW 3 of 8 2.4. Clinical Studies has been observed for tafenoquine 3 against a few hours for primaquine 2 [12]. Consequently, As early as 1998, tafenoquine 3 was administered, under the control of the Walter Reed Army comparable anti-plasmodial efficacy can be attained in humans with a single dose only of 300 mg of Institute3 of, whereas Research, primaquine to 48 healthy (2) must adultbe administered men in
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