Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Malaria Journal
Published in: Malaria Journal 1/2019

Open Access 01-12-2019 | Chloroquin | Review

The past, present and future of anti-malarial medicines

Authors: Edwin G. Tse, Marat Korsik, Matthew H. Todd

Published in: Malaria Journal | Issue 1/2019

Login to get access

Abstract

Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Shanks GD, Edstein MD, Jacobus D. Evolution from double to triple-antimalarial drug combinations. Trans R Soc Trop Med Hyg. 2014;109:182–8.PubMedCrossRef
5.
Mishra M, Mishra VK, Kashaw V, Iyer AK, Kashaw SK. Comprehensive review on various strategies for antimalarial drug discovery. Eur J Med Chem. 2017;125:1300–20.PubMedCrossRef
6.
Phillips MA, Burrows JN, Manyando C, van Huijsduijnen RH, Voorhis WCV, Wells TNC. Malaria. Nat Rev Dis Primers. 2017;3:17050.PubMedCrossRef
7.
8.
9.
10.
Williamson AE, Ylioja PM, Robertson MN, Antonova-Koch Y, Avery V, Baell JB, et al. Open source drug discovery: highly potent antimalarial compounds derived from the Tres Cantos arylpyrroles. ACS Cent Sci. 2016;2:687–701.PubMedPubMedCentralCrossRef
11.
Leong FJ, Li R, Jain JP, Lefèvre G, Magnusson B, Diagana TT, et al. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob Agents Chemother. 2014;58:6209–14.PubMedPubMedCentralCrossRef
12.
Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144.PubMedPubMedCentralCrossRef
13.
Bunnag D, Karbwang J, Na-Bangchang K, Thanavibul A, Chittamas S, Harinasuta T. Quinine-tetracycline for multidrug resistant falciparum malaria. Southeast Asian J Trop Med Public Health. 1996;27:15–8.PubMed
14.
15.
Green R. A report on fifty cases of malaria treated with Atebrin. A new synthetic drug. Lancet. 1932;219:826–9.CrossRef
16.
Guttman P, Ehrlich P. Ueber die wirkung des methylenblau bei malaria. Berl Klin Wochenschr. 1891;28:953–6.
17.
Schirmer RH, Coulibaly B, Stich A, Scheiwein M, Merkle H, Eubel J, et al. Methylene blue as an antimalarial agent. Redox Rep. 2003;8:272–5.PubMedCrossRef
18.
Lu G, Nagbanshi M, Goldau N, Jorge MM, Meissner P, Jahn A, et al. Efficacy and safety of methylene blue in the treatment of malaria: a systematic review. BMC Med. 2018;16:59.PubMedPubMedCentralCrossRef
19.
Weina PJ. From atabrine in World War II to mefloquine in Somalia: the role of education in preventive medicine. Mil Med. 1998;163:635–9.PubMedCrossRef
20.
Loeb F. Activity of a new antimalarial agent, chloroquine (SN 7618). JAMA. 1946;130:1069–70.CrossRef
21.
Mushtaque M. Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review. Eur J Med Chem. 2015;90:280–95.PubMedCrossRef
22.
Trenholme C, Williams R, Desjardins R, Frischer H, Carson P, Rieckmann K, et al. Mefloquine (WR 142,490) in the treatment of human malaria. Science. 1975;190:792–4.PubMedCrossRef
23.
Brasseur P, Druilhe P, Kouamouo J, Brandicourt O, Danis M, Moyou SR. High level of sensitivity to chloroquine of 72 Plasmodium falciparum isolates from southern Cameroon in January 1985. Am J Trop Med Hyg. 1986;35:711–6.PubMedCrossRef
24.
Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance. Int J Parasitol. 1997;27:231–40.PubMedCrossRef
25.
26.
Cosgriff TM, Desjardins RE, Pamplin CL, Canfield CJ, Doberstyn EB, Boudreau EF. Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669)*. Am J Trop Med Hyg. 1982;31:1075–9.PubMedCrossRef
27.
28.
Qinghaosu Antimalaria Coordinating Research Group. Antimalarial studies on Qinghaosu. Chin Med J (Engl ). 1979;92:811–6.
29.
30.
31.
Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant aalaria in western Cambodia. N Engl J Med. 2008;359:2619–20.PubMedCrossRef
32.
Amato R, Pearson RD, Almagro-Garcia J, Amaratunga C, Lim P, Suon S, et al. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. Lancet Infect Dis. 2018;18:337–45.PubMedPubMedCentralCrossRef
33.
34.
Wang J, Zhang CJ, Chia WN, Loh CCY, Li Z, Lee YM, et al. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun. 2015;6:10111.PubMedCrossRef
35.
36.
Shandilya A, Chacko S, Jayaram B, Ghosh I. A plausible mechanism for the antimalarial activity of artemisinin: a computational approach. Sci Rep. 2013;3:2513.PubMedPubMedCentralCrossRef
37.
Mok S, Ashley EA, Ferreira PE, Zhu L, Lin Z, Yeo T, et al. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2014;347:431–5.PubMedPubMedCentralCrossRef
38.
Mbengue A, Bhattacharjee S, Pandharkar T, Liu H, Estiu G, Stahelin RV, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015;520:683–7.PubMedPubMedCentralCrossRef
39.
Berliner RW, Earle DP, Taggart JV, Zubrod CG, Welch WJ, Conan NJ, et al. Studies on the chemotheraphy of the human malarias. VI. The physiological disposition, antimalarial activity, and toxicity of several derivatives of 4-aminoquinoline. J Clin Invest. 1948;27:98–107.PubMedPubMedCentralCrossRef
40.
Bompart F, Kiechel JR, Sebbag R, Pecoul B. Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience. Malar J. 2011;10:143.PubMedPubMedCentralCrossRef
41.
Combrinck JM, Mabotha TE, Ncokazi KK, Ambele MA, Taylor D, Smith PJ, et al. Insights into the role of heme in the mechanism of action of antimalarials. ACS Chem Biol. 2012;8:133–7.PubMedPubMedCentralCrossRef
42.
Chen L, Qu FY, Zhou YC. Field observations on the antimalarial piperaquine. Chin Med J (Engl ). 1982;95:281–6.PubMed
43.
Vennerstrom JL, Ellis WY, Ager AL, Andersen SL, Gerena L, Milhous WK. Bisquinolines. 1. N,N-Bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria. J Med Chem. 1992;35:2129–34.PubMedCrossRef
44.
45.
Curd FHS, Davey DG, Rose FL. Studies on synthetic antimalarial drugs. Ann Trop Med Parasitol. 1945;39:208–16.PubMedCrossRef
46.
Hudson AT, Randall AW. Naphthoquinone derivatives. US5053432A; 1991.
47.
Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4’-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol. 1992;43:1545–53.PubMedCrossRef
48.
Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother. 1999;43:1334–9.PubMedPubMedCentralCrossRef
49.
Russell PB, Hitchings GH. 2,4-Diaminopyrimidines as antimalarials. III. 5-Aryl derivatives. J Am Chem Soc. 1951;73:3763–70.CrossRef
50.
51.
52.
Lumb V, Das MK, Singh N, Dev V, Khan W, Sharma YD. Multiple origins of Plasmodium falciparum dihydropteroate synthetase mutant alleles associated with sulfadoxine resistance in India. Antimicrob Agents Chemother. 2011;55:2813–7.PubMedPubMedCentralCrossRef
53.
Zheng XY, Xia Y, Gao FH, Chen C. Synthesis of 7351, a new antimalarial drug. Yao Xue Xue Bao. 1979;14:736–7.PubMed
54.
Chang C, Lin-Hua T, Jantanavivat C. Studies on a new antimalarial compound: pyronaridine. Trans R Soc Trop Med Hyg. 1992;86:7–10.PubMedCrossRef
55.
Croft SL, Duparc S, Arbe-Barnes SJ, Craft J, Shin CS, Fleckenstein L, et al. Review of pyronaridine anti-malarial properties and product characteristics. Malar J. 2012;11:270.PubMedPubMedCentralCrossRef
56.
57.
Ebstie YA, Abay SM, Tadesse WT, Ejigu DA. Tafenoquine and its potential in the treatment and relapse prevention of Plasmodium vivax malaria: the evidence to date. Drug Des Devel Ther. 2016;10:2387–99.PubMedPubMedCentralCrossRef
58.
59.
Wells TNC, Gutteridge WE. Neglected diseases and drug discovery. Palmer MJ, Wells TNC, editors. RSC; 2012.
60.
Burrows JN, Duparc S, Gutteridge WE, van Huijsduijnen RH, Kaszubska W, Macintyre F, et al. New developments in anti-malarial target candidate and product profiles. Malar J. 2017;16:26.PubMedPubMedCentralCrossRef
61.
McChesney JD, Nanayakkara DNP, Bartlett M, Ager AL. Preparation of 8-(aminoalkylamino)quinolines as parasiticides. WO 9736590 A1; 1997.
62.
Tekwani BL, Walker LA. 8-Aminoquinolines: future role as antiprotozoal drugs. Curr Opin Infect Dis. 2006;19:623–31.PubMedCrossRef
63.
Nanayakkara NPD, Ager AL, Bartlett MS, Yardley V, Croft SL, Khan IA, et al. Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. Antimicrob Agents Chemother. 2008;52:2130–7.PubMedPubMedCentralCrossRef
64.
Marcsisin SR, Sousa JC, Reichard GA, Caridha D, Zeng Q, Roncal N, et al. Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds. Malar J. 2014;13:2.PubMedPubMedCentralCrossRef
65.
Powles MA, Allocco J, Yeung L, Nare B, Liberator P, Schmatz D. MK-4815, a potential new oral agent for treatment of malaria. Antimicrob Agents Chemother. 2012;56:2414–9.PubMedPubMedCentralCrossRef
66.
Singh C, Puri SK. Substituted 1,2,4-trioxanes as antimalarial agents and a process of producing the substituted 1,2,4-trioxanes. US6316493 B1; 2001.
67.
Shafiq N, Rajagopalan S, Kushwaha HN, Mittal N, Chandurkar N, Bhalla A, et al. Single ascending dose safety and pharmacokinetics of CDRI-97/78: first-in-human study of a novel antimalarial drug. Malar Res Treat. 2014;2014:372521.PubMedPubMedCentral
68.
O’Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK, et al. Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4’-fluoro and 4’-chloro analogues of amodiaquine. Identification of a suitable “back-up” compound for N-tert-butyl isoquine. J Med Chem. 2009;52:1828–44.PubMedCrossRef
69.
Bora S, Chetia D, Prakash A. Synthesis and antimalarial activity evaluation of some isoquine analogues. Med Chem Res. 2010;20:1632–7.CrossRef
70.
O’Neill PM, Park BK, Shone AE, Maggs JL, Roberts P, Stocks PA, et al. Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century. J Med Chem. 2009;52:1408–15.PubMedCrossRef
71.
Haynes RK, Fugmann B, Stetter J, Rieckmann K, Heilmann HD, Chan HW, et al. Artemisone—a highly active antimalarial drug of the artemisinin class. Angew Chem Int Ed. 2006;45:2082–8.CrossRef
72.
Nicolas O, Margout D, Taudon N, Wein S, Calas M, Vial HJ, et al. Pharmacological properties of a new antimalarial bisthiazolium salt, T3, and a corresponding prodrug, TE3. Antimicrob Agents Chemother. 2005;49:3631–9.PubMedPubMedCentralCrossRef
73.
Drake NL, Creech HJ, Garman JA, Haywood ST, Peck RM, van Hook JO, et al. Synthetic antimalarials. The preparation of certain 4-aminoquinolines\(^{1}\). J Am Chem Soc. 1946;68:1208–13.PubMedCrossRef
74.
Ramanathan-Girish S, Catz P, Creek MR, Wu B, Thomas D, Krogstad DJ, et al. Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques. Int J Toxicol. 2004;23:179–89.PubMedCrossRef
75.
Sáenz FE, Mutka T, Udenze K, Oduola AMJ, Kyle DE. Novel 4-aminoquinoline analogs highly active against the blood and sexual stages of Plasmodium in vivo and in vitro. Antimicrob Agents Chemother. 2012;56:4685–92.PubMedPubMedCentralCrossRef
76.
Mzayek F, Deng H, Mather FJ, Wasilevich EC, Liu H, Hadi CM, et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials. 2007;2:e6.PubMedPubMedCentralCrossRef
77.
Koita OA, Sangaré L, Miller HD, Sissako A, Coulibaly M, Thompson TA, et al. AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial. Lancet Infect Dis. 2017;17:1266–75.PubMedPubMedCentralCrossRef
78.
Baragaña B, Hallyburton I, Lee MCS, Norcross NR, Grimaldi R, Otto TD, et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015;522:315–20.PubMedPubMedCentralCrossRef
79.
Baragaña B, Norcross NR, Wilson C, Porzelle A, Hallyburton I, Grimaldi R, et al. Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. J Med Chem. 2016;59:9672–85.PubMedPubMedCentralCrossRef
80.
Burrows JN, van Huijsduijnen RH, Möhrle JJ, Oeuvray C, Wells TN. Designing the next generation of medicines for malaria control and eradication. Malar J. 2013;12:187.PubMedPubMedCentralCrossRef
81.
Hameed PS, Solapure S, Patil V, Henrich PP, Magistrado PA, Bharath S, et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun. 2015;6:6715.CrossRef
82.
83.
Manach CL, Nchinda AT, Paquet T, Cabrera DG, Younis Y, Han Z, et al. Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle. J Med Chem. 2016;59:9890–905.PubMedCrossRef
84.
Younis Y, Douelle F, Feng TS, Cabrera DG, Manach CL, Nchinda AT, et al. 3,5-Diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential. J Med Chem. 2012;55:3479–87.PubMedCrossRef
85.
Cabrera DG, Douelle F, Younis Y, Feng TS, Manach CL, Nchinda AT, et al. Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines. J Med Chem. 2012;55:11022–30.CrossRef
86.
Younis Y, Douelle F, Cabrera DG, Manach CL, Nchinda AT, Paquet T, et al. Structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity. J Med Chem. 2013;56:8860–71.PubMedCrossRef
87.
88.
Zhang YK, Plattner JJ, Freund YR, Easom EE, Zhou Y, Gut J, et al. Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents. Bioorg Med Chem Lett. 2011;21:644–51.PubMedCrossRef
89.
Zhang YK, Plattner JJ, Easom EE, Jacobs RT, Guo D, Freund YR, et al. Benzoxaborole antimalarial agents. Part 5. Lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate. J Med Chem. 2017;60:5889–908.PubMedCrossRef
90.
Zhang YK, Plattner JJ, Easom EE, Jacobs RT, Guo D, Sanders V, et al. Benzoxaborole antimalarial agents. Part 4. Discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles. J Med Chem. 2015;58:5344–54.PubMedPubMedCentralCrossRef
91.
Sonoiki E, Ng CL, Lee MCS, Guo D, Zhang YK, Zhou Y, et al. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. Nat Commun. 2017;8:14574.PubMedPubMedCentralCrossRef
92.
Pegoraro S, Duffey M, Otto TD, Wang Y, Rösemann R, Baumgartner R, et al. SC83288 is a clinical development candidate for the treatment of severe malaria. Nat Commun. 2017;8:14193.PubMedPubMedCentralCrossRef
93.
Leban J, Pegoraro S, Dormeyer M, Lanzer M, Aschenbrenner A, Kramer B. Sulfonyl-phenyl-ureido benzamidines. Bioorg Med Chem Lett. 2004;14:1979–82.PubMedCrossRef
94.
Duffey M, Sanchez CP, Lanzer M. Profiling of the anti-malarial drug candidate SC83288 against artemisinins in Plasmodium falciparum. Malar J. 2018;17:121.PubMedPubMedCentralCrossRef
95.
Burgess SJ, Kelly JX, Shomloo S, Wittlin S, Brun R, Liebmann K, et al. Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds. J Med Chem. 2010;53:6477–89.PubMedPubMedCentralCrossRef
96.
Burgess SJ, Selzer A, Kelly JX, Smilkstein MJ, Riscoe MK, Peyton DH. A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum. J Med Chem. 2006;49:5623–5.PubMedPubMedCentralCrossRef
97.
Wirjanata G, Sebayang BF, Chalfein F, Prayoga, Handayuni I, Noviyanti R, et al. Contrasting ex vivo efficacies of “reversed chloroquine” compounds in chloroquine-resistant Plasmodium falciparum and P. vivax isolates. Antimicrob Agents Chemother. 2015;59:5721–6.PubMedPubMedCentralCrossRef
98.
Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, et al. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci USA. 2012;109:16823–8.PubMedCrossRefPubMedCentral
99.
100.
Floyd DM, Stein P, Wang Z, Liu J, Castro S, Clark JA, et al. Hit-to-lead studies for the antimalarial tetrahydroisoquinolone carboxanilides. J Med Chem. 2016;59:7950–62.PubMedPubMedCentralCrossRef
101.
Jiménez-Díaz MB, Ebert D, Salinas Y, Pradhan A, Lehane AM, Myrand-Lapierre ME, et al. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc Natl Acad Sci USA. 2014;111:E5455–62.PubMedCrossRefPubMedCentral
102.
Spillman NJ, Kirk K. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs. Int J Parasitol Drugs Drug Resist. 2015;5:149–62.PubMedPubMedCentralCrossRef
103.
Boss C, Aissaoui H, Amaral N, Bauer A, Bazire S, Binkert C, et al. Discovery and characterization of ACT-451840: an antimalarial drug with a novel mechanism of action. ChemMedChem. 2016;11:1995–2014.PubMedCrossRef
104.
Bihan AL, de Kanter R, Angulo-Barturen I, Binkert C, Boss C, Brun R, et al. Characterization of novel antimalarial compound ACT-451840: preclinical assessment of activity and dose-efficacy modeling. PLoS Med. 2016;13:e1002138.PubMedPubMedCentralCrossRef
105.
Krause A, Dingemanse J, Mathis A, Marquart L, Möhrle JJ, McCarthy JS. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion-451840 in an induced blood stage malaria study in healthy subjects. Br J Clin Pharmacol. 2016;82:412–21.PubMedPubMedCentralCrossRef
106.
Charman SA, Arbe-Barnes S, Bathurst IC, Brun R, Campbell M, Charman WN, et al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci USA. 2011;108:4400–5.PubMedCrossRefPubMedCentral
107.
Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FCK, Chollet J, et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004;430:900–4.PubMedCrossRef
108.
Dong Y, Wittlin S, Sriraghavan K, Chollet J, Charman SA, Charman WN, et al. The structure-activity relationship of the antimalarial ozonide Arterolane (OZ277). J Med Chem. 2010;53:481–91.PubMedCrossRef
109.
Dong Y, Chollet J, Matile H, Charman SA, Chiu FCK, Charman WN, et al. Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes. J Med Chem. 2005;48:4953–61.PubMedCrossRef
110.
Dong Y, Tang Y, Chollet J, Matile H, Wittlin S, Charman SA, et al. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg Med Chem. 2006;14:6368–82.PubMedCrossRef
111.
Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, et al. Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160). Antimicrob Agents Chemother. 2007;51:2991–3.PubMedPubMedCentralCrossRef
112.
Dong Y, Wang X, Kamaraj S, Bulbule VJ, Chiu FCK, Chollet J, et al. Structure-activity relationship of the antimalarial ozonide Artefenomel (OZ439). J Med Chem. 2017;60:2654–68.PubMedCrossRef
113.
Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16:61–9.PubMedPubMedCentralCrossRef
114.
Gautam A, Ahmed T, Sharma P, Varshney B, Kothari M, Saha N, et al. Pharmacokinetics and pharmacodynamics of Arterolane maleate following multiple oral doses in adult patients with P. falciparum malaria. J Clin Pharmacol. 2011;51:1519–28.PubMedCrossRef
115.
Valecha N, Krudsood S, Tangpukdee N, Mohanty S, Sharma SK, Tyagi PK, et al. Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated lasmodium falciparum malaria: a comparative, multicenter, randomized clinical trial. Clin Infect Dis. 2012;55:663–71.PubMedCrossRef
116.
Jourdan J, Matile H, Reift E, Biehlmaier O, Dong Y, Wang X, et al. Monoclonal antibodies that recognize the alkylation signature of antimalarial ozonides OZ277 (Arterolane) and OZ439 (Artefenomel). ACS Infect Dis. 2015;2:54–61.PubMedPubMedCentralCrossRef
117.
Allman EL, Painter HJ, Samra J, Carrasquilla M, Llinás M. Metabolomic profiling of the malaria box reveals antimalarial target pathways. Antimicrob Agents Chemother. 2016;60:6635–49.PubMedPubMedCentralCrossRef
118.
Moehrle JJ, Duparc S, Siethoff C, van Giersbergen PLM, Craft JC, Arbe-Barnes S, et al. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol. 2013;75:535–48.CrossRef
119.
McCarthy JS, Baker M, O’Rourke P, Marquart L, Griffin P, van Huijsduijnen RH, et al. Efficacy of OZ439 (Artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother. 2016;71:2620–7.PubMedPubMedCentralCrossRef
120.
Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, et al. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc Natl Acad Sci USA. 2008;105:9059–64.PubMedCrossRefPubMedCentral
121.
Nagle A, Wu T, Kuhen K, Gagaring K, Borboa R, Francek C, et al. Imidazolopiperazines: lead optimization of the second-generation antimalarial agents. J Med Chem. 2012;55:4244–73.PubMedPubMedCentralCrossRef
122.
Wu T, Nagle A, Kuhen K, Gagaring K, Borboa R, Francek C, et al. Imidazolopiperazines: hit to lead optimization of new antimalarial agents. J Med Chem. 2011;54:5116–30.PubMedCrossRefPubMedCentral
123.
Kuhen KL, Chatterjee AK, Rottmann M, Gagaring K, Borboa R, Buenviaje J, et al. KAF156 Is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob Agents Chemother. 2014;58:5060–7.PubMedPubMedCentralCrossRef
124.
Rottmann M, McNamara C, Yeung BKS, Lee MCS, Zou B, Russell B, et al. Spiroindolones, a potent compound class for the treatment of malaria. Science. 2010;329:1175–80.PubMedPubMedCentralCrossRef
125.
Yeung BKS, Zou B, Rottmann M, Lakshminarayana SB, Ang SH, Leong SY, et al. Spirotetrahydro \(\beta\)-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem. 2010;53:5155–64.PubMedCrossRefPubMedCentral
126.
White NJ, Pukrittayakamee S, Phyo AP, Rueangweerayut R, Nosten F, Jittamala P, et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med. 2014;371:403–10.PubMedPubMedCentralCrossRef
127.
Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, et al. Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem. 2011;54:5540–61.PubMedPubMedCentralCrossRef
128.
McCarthy JS, Lotharius J, Rückle T, Chalon S, Phillips MA, Elliott S, et al. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis. 2017;17:626–35.PubMedPubMedCentralCrossRef
129.
Nigussie D, Beyene T, Shah NA, Belew S. New targets in malaria parasite chemotherapy: a review. Malaria Contr Elimination. 2015;S1:S1–007.CrossRef
130.
Jorgensen R, Merrill AR, Andersen GR. The life and death of translation elongation factor 2. Biochem Soc Trans. 2006;34:1–6.PubMedCrossRef
131.
Spillman NJ, Allen RJW, McNamara CW, Yeung BKS, Winzeler EA, Diagana TT, et al. Na\(^+\) Regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe. 2013;13:227–37.PubMedPubMedCentralCrossRef
132.
133.
Voorhis WCV, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P, et al. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond. PLoS Pathog. 2016;12:e1005763.PubMedPubMedCentralCrossRef
134.
Dennis ASM, Rosling JEO, Lehane AM, Kirk K. Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis. Sci Rep. 2018;8:8795.PubMedPubMedCentralCrossRef
135.
Saliba KJ, Kirk K. pH Regulation in the intracellular malaria parasite Plasmodium falciparum. J Biol Chem. 1999;274:33213–9.PubMedCrossRef
136.
Baldwin J, Farajallah AM, Malmquist NA, Rathod PK, Phillips MA. Malarial dihydroorotate dehydrogenase. J Biol Chem. 2002;277:41827–34.PubMedCrossRef
137.
Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med. 2015;7:296ra111.PubMedPubMedCentralCrossRef
138.
Yuthavong Y, Yubaniyama J, Chitnumsub P, Vanichtanankul J, Chusacultanachai S, Tarnchompoo B, et al. Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors. Parasitology. 2005;130:249–59.PubMedCrossRef
139.
Luth MR, Gupta P, Ottilie S, Winzeler EA. Using in vitro evolution and whole genome analysis to discover next generation targets for antimalarial drug discovery. ACS Infect Dis. 2018;4:301–14.PubMedPubMedCentralCrossRef
140.
Metadata
Title
The past, present and future of anti-malarial medicines
Authors
Edwin G. Tse
Marat Korsik
Matthew H. Todd
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2019
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-019-2724-z

Other articles of this Issue 1/2019

Malaria Journal 1/2019 Go to the issue

Research

Safety of primaquine in infants with Plasmodium vivax malaria in Papua, Indonesia

Research

Differential expression of var subgroups and PfSir2a genes in afebrile Plasmodium falciparum malaria: a matched case–control study

Correction

Correction to: Performance of an ultra-sensitive Plasmodium falciparum HRP2-based rapid diagnostic test with recombinant HRP2, culture parasites, and archived whole blood samples

Research

Immunoglobulin G subclass and antibody avidity responses in Malian children immunized with Plasmodium falciparum apical membrane antigen 1 vaccine candidate FMP2.1/AS02A

Research

Synergy and timing: a concurrent mass medical campaign predicted to augment indoor residual spraying for malaria

Research

Strengthening surveillance systems for malaria elimination: a global landscaping of system performance, 2015–2017

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits