pharmaceuticals

Brief Report Tafenoquine: A 2018 Novel FDA-Approved Prodrug for the Radical Cure of vivax 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 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. (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, -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. (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 asInternational 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 4 LLC-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 vivax Kodatef® 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 activity addition, ofthe primaquine ortho-quinone ( 24) was and detected tafenoquine (3) is thoughtduring toThere be a related pharmacokinetic 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 (Figure deficiency, 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 (hemolytic had 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 in ether 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 order daily to(15 evaluate mg) for two its weeks safety [2 and]. efficacy and to collect pharmacokinetics data [13]. Later on, GSK sponsored the first clinical trial recorded in the National Institutes2.4. of Clinical Health Studies (NIH) data [14] for tafenoquine. It was initiated in March 2009 (NCT00871156) under the offiAscial early title as 1998, “Safety, tafenoquine Tolerability, 3 was andadministered Pharmacokinetic, under the control Study of the Concomitant Walter Reed ChloroquineArmy and TafenoquineInstitute of Research, in Healthy to 48 Volunteers”.healthy adult men It in was order a to phase evaluate 1 studyits safety involving and efficacy 68 and participants to collect and was describedpharmacokinetics in the paper data [13] of. MillerLater on, et GSK al. [sponsor15] in 2013.ed the first The clinical trial hastrial beenrecorded followed in the National by five other completedInstitutes phase of 1 Health studies, (NIH five) data completed [14] for phasetafenoquine. 2 studies, It was and initiated only in one March [16] 2009 completed (NCT00871156) phase 3 study. under the official title “Safety, Tolerability, and Pharmacokinetic Study of Concomitant Chloroquine Hemolysis risks (NCT01205178 and NCT02216123) and retinal effects (NCT02658435) were among and Tafenoquine in Healthy Volunteers”. It was a phase 1 study involving 68 participants and was specificdescribed side-effects in the targeted paper of inMiller those et al. investigations. [15] in 2013. The trial Both has companies been followed commercializing by five other completed tafenoquine (GlaxoSmithKlinephase 1 studies, and five60 Degrees completed Pharmaceuticals phase 2 studies, LLC)and onl arey one actually [16] completed recruiting phase volunteers 3 study. for two phase 2Hemolysis studies (NCT03320174 risks (NCT01205178 and NCT02563496)and NCT02216123) and and one retinal phase effects 3 study (NCT02658435) (NCT02802501). were among specific side-effects targeted in those investigations. Both companies commercializing tafenoquine 2.5. Syntheses(GlaxoSmithKline and 60 Degrees Pharmaceuticals LLC) are actually recruiting volunteers for two phase 2 studies (NCT03320174 and NCT02563496) and one phase 3 study (NCT02802501). Historically, the key intermediate in the preparation of tafenoquine is 4-methyl-5-(3- trifluoromethylphenoxy)-6-methoxy-8-aminoquinoline2.5. Syntheses 12 (Scheme1). Two alternate routes have been describedHistorically, to access the that key derivative. intermediate in the preparation of tafenoquine is 4-methyl-5-(3- Onetrifluoromethylphenoxy) route (Scheme1) started-6-methoxy from veratrol-8-aminoquinoline ( 5)[17]. 1 It2 was(Scheme nitrated 1). Two in positions alternate 4 routes and 5. have One nitro group wasbeen reduced described by to treatment access that withderivative. ammonia in methanol and the quinoline system 8 was built by a Skraup reactionOne route involving (Scheme methyl 1) started vinyl from ketone. veratrol The(5) [1 5-methoxy7]. It was nitrated group in positions was selectively 4 and 5. One demethylated nitro group was reduced by treatment with ammonia in methanol and the quinoline system 8 was built by and the hydroxy derivative was converted to the 5-chloroquinoline 10 by phosphorus oxychloride. a Skraup reaction involving methyl vinyl ketone. The 5-methoxy group was selectively demethylated Subsequentand the action hydroxy of 3-hydroxybenzotrifluoride derivative was converted to the and 5-chloroqui reductionnoline of the10 by 8-nitro phosphorus group oxychloride. afforded the key intermediateSubsequent12 in action an overall of 3-hydroxybenzotrifluoride yield of 7%. and reduction of the 8-nitro group afforded the key intermediate 12 in an overall yield of 7%.

Scheme 1. Preparation of compound 12 from veratrol.

The alternate route (Scheme2) started from 2-fluoroanisole ( 13)[17]. The compound was nitrated and the nitro group was reduced to the aniline 15. Deactivation of the amino function was achieved by acetylation allowing nitration in position 5. Deacetylation of 17 followed by the Skraup reaction Pharmaceuticals 2019, 12, x FOR PEER REVIEW 4 of 8

Pharmaceuticals 2019, 12, 115 Scheme 1. Preparation of compound 12 from veratrol. 4 of 7

The alternate route (Scheme 2) started from 2-fluoroanisole (13) [17]. The compound was nitrated and the nitro group was reduced to the aniline 15. Deactivation of the amino function was afforded theachieved 5-fluoroquinoline by acetylation allowing19. Fluorine nitration displacement in position 5. Deacetylation by 3-hydroxybenzotrifluoride of 17 followed by the Skraup followed by reduction ofreaction the 8-nitro afforded group the 5 yielded-fluoroquinoline12 with 19. 8% Fluorine overall displacement yield. by 3-hydroxybenzotrifluoride followed by reduction of the 8-nitro group yielded 12 with 8% overall yield.

SchemeScheme 2. Preparation 2. Preparation of of compound compound 12 12fromfrom 2-fluoroanisole. 2-fluoroanisole.

In order toIn introduce order to introduce the second the second methoxy methoxy moietymoiety in inposition position 2 (Scheme 2 (Scheme 3), the 8-3amino), the group 8-amino group was protected by conversion into the phthalimido compound 20. Formation of the quinoline N-oxide was protected21 byenabl conversioned chlorination into in the position phthalimido 2 of the fused compound heterocyclic20 system,. Formation eventually of through the quinoline the N-oxide 21 enabled chlorinationquinolone 22. After in deprotectionposition2 of of the the 8-amino fused function, heterocyclic treatment withsystem, sodium eventually hydride and through the quinolone 22methanol. After (or deprotection sodium methoxide) of yielded the 8-amino the 2-methoxy function, derivative treatment 25 [18]. with sodium hydride and methanol (or sodium methoxide) yielded the 2-methoxy derivative 25 [18]. Pharmaceuticals 2019, 12, x FOR PEER REVIEW 5 of 8

SchemeScheme 3. Preparation 3. Preparation ofof the the 8- 8-aminoquinolineaminoquinoline 25. 25.

Finally, tafenoquine 3 has been obtained (Scheme 4) by alkylation of compound 25 through three different routes involving (i) action of N-(4-iodopentyl)phthalimide and subsequent hydrazinolysis of the phthalimido group [18–20]; (ii) reductive amination by N-(4-oxopentyl)phthalimide and subsequent hydrazinolysis [21]; or (iii) reductive amination by 5-nitropentan-2-one followed by reduction of the nitro group [21]. Treatment of 3, isolated or not, with succinic acid afforded the commercial succinate salt of tafenoquine.

Pharmaceuticals 2019, 12, 115 5 of 7

Finally, tafenoquine 3 has been obtained (Scheme4) by alkylation of compound 25 through three different routes involving (i) action of N-(4-iodopentyl)phthalimide and subsequent hydrazinolysis of the phthalimido group [18–20]; (ii) reductive amination by N-(4-oxopentyl)phthalimide and subsequent hydrazinolysis [21]; or (iii) reductive amination by 5-nitropentan-2-one followed by reduction of the nitro group [21]. Treatment of 3, isolated or not, with succinic acid afforded the commercial succinate salt ofPharmaceuticals tafenoquine. 2019, 12, x FOR PEER REVIEW 6 of 8

Scheme 4. ThreeThree strategies strategies yielding yielding tafenoquine tafenoquine 3 fromfrom the the 8 8-aminoquinoline-aminoquinoline 25.25.

3. Perspectives3. Perspectives MentionMention should should be be made made that, that, contrarycontrary to primaquine, tafenoquine tafenoquine 3 can3 can inhibit inhibit hematin hematin polymerizationpolymerization and and therefore therefore can can exhibit, exhibit, in in additionaddition to to its its hypnozoiticidal hypnozoiticidal action, action, an antiplasmodial an antiplasmodial activityactivity during during the the blood blood stage stage of of the the parasite parasite [22]].. Consequently, Consequently, several several clinical clinical trials trials are dedicated are dedicated to evaluationsto evaluations of tafenoquine, of tafenoquine, alone alone or or in in combinations, combinations, forfor malariamalaria prophylaxi prophylaxiss [23 [23] and] and treatment treatment of of P. falciparum parasitaemia (NCT02488902, NCT02488980, and NCT02491606). P. falciparum parasitaemia (NCT02488902, NCT02488980, and NCT02491606). Author Contributions: Both authors contributed equally to this manuscript.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest

References

Pharmaceuticals 2019, 12, 115 6 of 7

Author Contributions: Both authors contributed equally to this manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest

References

1. World Malaria Report 2018. Available online: https://www.who.int/malaria/publications/world-malaria- report-2018/report/en/ (accessed on 19 November 2018). 2. Campo, B.; Vandal, O.; Wesche, D.L.; Burrows, J.N. Killing the Hypnozoite—Drug Discovery Approaches to Prevent Relapse in Plasmodium vivax. Pathog. Glob. Health 2015, 109, 107–122. [CrossRef] 3. World Health Organization. Guidelines for the Treatment of Malaria, 3rd ed.; World Health Organization: Geneva, Switzerland, 2015; Volume 9, pp. 93–95. 4. Allgower, A.; Taylor, W.R.; Chappuis, F.; Eperon, G. Plasmodium vivax, un Parasite qui Sort de l’Ombre. Rev. Med. Suisse 2016, 12, 876–881. [PubMed] 5. Krintafel (Tafenoquine)—FDA. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2018/210795s000lbl.pdf (accessed on 16 July 2019). 6. Arakoda (Tafenoquine) Tablets—FDA. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2018/210607lbl.pdf (accessed on 16 July 2019). 7. Marcsisin, S.R.; Reichard, G.; Pybus, B.S. Primaquine Pharmacology in the Context of CYP 2D6 Pharmacogenomics: Current State of the Art. Pharmacol. Ther. 2016, 161, 1–10. [CrossRef][PubMed] 8. Marcsisin, S.R.; Sousa, J.C.; Reichard, G.A.; Caridha, D.; Zeng, Q.; Roncal, N.; McNulty, R.; Careagabarja, J.; Sciotti, R.J.; Bennett, J.W.; et al. Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds. Malaria J. 2014, 13, 2. [CrossRef][PubMed] 9. Delves, M.; Plouffe, D.; Scheurer, C.; Meister, S.; Wittlin, S.; Winzeler, E.A.; Sinden, R.E.; Leroy,D. The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites. PLoS Med. 2012, 9, e1001169. [CrossRef][PubMed] 10. Vuong, C.; Xie, L.H.; Potter, B.M.J.; Zhang, J.; Zhang, P.; Duan, D.; Nolan, C.K.; Sciotti, R.J.; Zottig, V.E.; Nanayakkara, N.P.D.; et al. Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics. Antimicrob. Agents Chemother. 2015, 59, 3864–3869. [CrossRef][PubMed] 11. Watson, J.; Taylor, W.R.J.; Bancone, G.; Chu, C.S.; Jittamala, P.; White, N.J. Implications of Current Therapeutic Restrictions for Primaquine and Tafenoquine in the Radical Cure of vivax Malaria. PLoS Negl. Trop. Dis. 2018, 12, e0006440. [CrossRef][PubMed] 12. Li, Q.; O’Neil, M.; Xie, L.; Caridha, D.; Zeng, Q.; Zhang, J.; Pybus, B.; Hickman, M.; Melendez, V. Assessment of the Prophylactic Activity and Pharmacokinetic Profile of Oral Tafenoquine Compared to Primaquine for Inhibition of Liver Stage Malaria Infections. Malaria J. 2014, 13, 141. [CrossRef][PubMed] 13. Brueckner, R.P.; Lasseter, R.P.; Lin, E.T.; Schuste, B.G. First-Time-in-Humans Safety and Pharmacokinetics of WR 238605, a New Antimalarial. Am. J. Trop. Med. Hyg. 1998, 58, 645–649. [CrossRef][PubMed] 14. NIH US National Library of Medicine. Available online: https://www.clinicaltrials.gov/ct2/results?term= tafenoquine&age_v=&gndr=&type=&rslt=&Search=Apply (accessed on 16 July 2019). 15. Miller, A.K.; Harrell, E.; Ye, L.; Baptiste-Brown, S.; Kleim, J.P.; Ohrt, C.; Duparc, S.; Möhrle, J.J.; Webster, A.; Stinnett, S.; et al. Pharmacokinetic Interactions and Safety Evaluations of Coadministered Tafenoquine and Chloroquine in Healthy Subjects. Br. J. Clin. Pharmacol. 2013, 76, 858–867. [CrossRef][PubMed] 16. Llanos-Cuentas, A.; Lacerda, M.V.G.; Hien, T.T.; Vélez, I.D.; Namaik-larp, C.; Chu, C.S.; Villegas, M.F.; Val, F.; Monteiro, W.M.; Brito, M.A.M.; et al. Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N. Eng. J. Med. 2019, 380, 229–241. [CrossRef][PubMed] 17. 4-Methyl-5-(unsubstituted and substituted phenoxy)-6-methoxy-8-(aminoalkylamino)quinolines. Available online: https://patents.google.com/patent/US4431807A/en (accessed on 29 July 2019). 18. 4-Methyl-5-(unsubstituted and substituted phenoxy)-2,6-dimethoxy-8-(aminoalkylamino)quinolines. Available online: https://patents.google.com/patent/US4617394A/en (accessed on 29 July 2019). 19. Process for the Preparation of Anti-malarial Drugs. Available online: https://patents.google.com/patent/ WO1997013753A1/en (accessed on 29 July 2019). Pharmaceuticals 2019, 12, 115 7 of 7

20. Process for the Preparation of Anti-malarial Drugs. Available online: https://patents.google.com/patent/ US6479660B1/en (accessed on 29 July 2019). 21. Feline pancreatic lipase composition and method of preparing and using such composition. Available online: https://patents.google.com/patent/WO2003093232A2/en?oq=WO+03%2f093232+A2 (accessed on 29 July 2019). 22. Vennerstrom, J.L.; Nuzum, E.O.; Miller, R.E.; Dorn, A.; Gerena, L.; Dande, P.A.; Ellis, W.Y.; Ridley, R.G.; Milhous, W.K. 8-Aminoquinolines Active against Blood Stage Plasmodium falciparum in vitro Inhibit Hematin Polymerization. Antimicrob. Agents Chemother. 1999, 43, 598–602. [CrossRef] 23. Novitt-Moreno, A.; Ransom, J.; Dow, G.; Smith, B.; Read, L.T.; Toovey, S. Tafenoquine for in Adults: An Integrated Safety Analaysis. Travel Med. Infect. Dis. 2017, 17, 19–27. [CrossRef][PubMed]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).