Antiplasmodial Activity and Cytotoxicity of 10β-Aminoquinolinylethylethers of Artemisinin

Abstract

Background:

Each year roughly 800 000 people die of malaria, with 95% being African children. The shortcomings of the current drugs and the emergence of P. falciparum resistance to the artemisinin class of compounds warrant the search for new classes or derivatives. In search for such compounds, a series of 10β-amino­quinolinylethylethers of artemisinin, previously synthesized from this laboratory were screened for antimalarial activity against both the chloroquine-susceptible 3D7 and -resistant K1 strains of P. falciparum. Their cytotoxicity was also assessed against HEK 293 and HepG2 cell lines.

Methods:

The parasitic and mammalian cells were incubated with compounds at various concentrations for 72 h. The antimalarial activity was determined using SYBR Green I-based fluorescence. For cytotoxicity determination, cells were grown to confluence and CellTiter-Glo luminescent cell viability assay was used.

Results:

All derivatives proved to be active against both strains with good selectivity towards the parasitic cells. The derivative 11 featuring 2 artemisinin moieties and an aminoethylpiperazine linker was the most active of all. It possessed 17- and 166-fold more potency than artemether against 3D7 (EC₅₀: 9.5 vs. 166 nM) and K1 (10.9 vs. 1723.3 nM), respectively, while was found to be as potent as artesunate against both strains.

Conclusion:

Derivative 11 stands as a good candidate to be further investigated primarily in vitro in comparison with an equimolar combination of chloroquine (CQ) and artemisinin to ascertain its advantages, if any, over the combination.

Key words

malaria - P. falciparum - selectivity

• References

• 1 WHO, World Malaria Report 2011 ([Web:] http://www.who.int/malaria/ world_malaria_report_2011/9789241564403_eng.pdf [Date used: 7 February 2012]) 2011
• 2 White NJ. Qinghaosu (artemisinin): the price of success. Science 2008; 320: 330-334
• 3 Dondorp AM, Nosten F, Yi P et al. Artemisinin resistance in P. falciparum malaria. N Engl J Med 2009; 361: 455-467
• 4 Noedl H, Se Y, Schaecher K et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 2008; 359: 2619-2620
• 5 Noedl H, Se Y, Sriwichai S et al. Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia. Clin Infect Dis 2010; 51: e82-e89
• 6 Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med 2009; 361: 540-541
• 7 WHO World Health Organization . Development of a strategy towards elimination of Plasmodium falciparum parasites with altered responses to artemisinins. WHO 2009; 1-52
• 8 WHO World Health Organization . Strategic framework for artemisinin resistance containment in Myanmar (MARC) 2011–2015. WHO 2011; 1-97 http://www.who.int/malaria/publications/atoz/artemisinin_­resistance_containment_2011.pdf
• 9 Lin AJ, Klayman DL, Milhous WK. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. J Med Chem 1987; 30: 2147-2150
• 10 Leskovac V, Theoharides AD. Hepatic metabolism of artemisinin drugs – I. Drug metabolism in rat liver microsomes. Comp Biochem Physiol 1991; 99: 383-390
• 11 Leskovac V, Theoharides AD. Hepatic metabolism of artemisinin drugs – II. Metabolism of arteether in rat liver cytosol. Comp Biochem ­Physiol 1991; 99: 391-396
• 12 Baker JK, McChesney JD, Chi H-T. Decomposition of arteether in simulated stomach acid yielding compounds retaining antimalarial activity. Pharm Res 1993; 10: 662-666
• 13 Batty KT, IIett KF, Davis TME. Chemical stability of artesunate injection and proposal for its administration by intravenous infusion. J Pharm Pharmacol 1996; 48: 22-26
• 14 China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials . J Tradit Chin Med 1982; 2: 9-16
• 15 Li Y, Zhu Y-M, Jiang H-J et al. Synthesis and antimalarial activity of artemisinin derivatives containing an amino group. J Med Chem 2000; 43: 1635-1640 Haynes RK, Chan H-W, Cheung M-K, Lam W-L, Soo M-K, Tsang H-W, et al. C-10 Ester and ether derivatives of dihydroartemisinin -10-α artesunate, preparation of authentic 10-β artesunate, and of other ester and ether derivatives bearing potential aromatic intercalating groups at C-10. Eur J Org Chem 2002; 113-132; Hindley S, Ward SA, Storr RC, Searle NL, Bray PG, Park BK, et al. Mechanism-based design of parasite-targeted artemisinin derivatives:  Synthesis and antimalarial activity of new diamine containing analogues. J Med Chem 2002; 45: 1052-1063; Haynes RK, Chan H-W, Cheung M-K, Lam W-L, Soo M-K, Tsang H-W, et al. Stereoselective preparation of 10α- and 10β-aryl derivatives of dihydroartemisinin. Eur J Org Chem 2003; 2098-2114
• 16 Few reviews on clinical use, chemistry, pharmacology, and mode of action, see: Meshnick SR . Artemisinin: mechanisms of action, resistance and toxicity. Inter J Parasitol 2002; 32: 1655-1660 Gordi T, Lepist E-I. Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett 2004; 147: 99-107; PrayGod G, de Frey A, Eisenhut M. Artemisinin derivatives versus quinine in treating severe malaria in children: a systematic review. Malaria J 2008;7: 210; Chaturvedi D, Goswani A, Sakia PP, Barua NC, Rao PG. Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chem Soc Rev 2010; 39: 435-454
• 17 Enserink M. If artemisinin drugs fail, what’s plan B?. Science 2010; 328: 846
• 18 Coslédan F, Fraisse L, Pellet A et al. Selection of a trioxaquine as an antimalarial drug candidate. PNAS 2008; 105: 17579-17584
• 19 Vennerstrom JL, Arbe-Barnes S, Brun R et al. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004; 430: 900-904
• 20 Olliaro P, Wells TNC. The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther 2009; 85: 584-595
• 21 Valecha N, Krudsood S, Tangpukdee N et al. Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated P. falciparum Malaria: A comparative, multicenter, randomized clinical trial. Clin Infect Dis 2012; 55: 663-671
• 22 http://www.rsc.org/chemistryworld/2012/05/ranbaxy-launches-new-anti-malarial-synriam
• 23 Charman SA, Arbe-Barnes S, Bathurst IC et al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. PNAS Early Edition 2011; 1-6
• 24 Steyn M, N’Da DD, Breytenbach JC et al. Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin. J Pharm Pharmacol 2011; 63: 278-286
• 25 Lombard MC, N’Da DD, Breytenbach JC et al. Artemisinin-quinoline hybrid-dimers: Synthesis and in vitro antiplasmodial activity. Bioorg Med Chem Lett 2010; 20: 6975-6977
• 26 Lombard MC, N’Da DD, Breytenbach JC et al. Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids. Bioorg Med Chem Lett 2011; 21: 1683-1686
• 27 Cloete TT, Breytenbach JW, de Kock C et al. Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin. Bioorg Med Chem 2012; 20: 4701-4709
• 28 Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976; 193: 673-675
• 29 Smilkstein M, Sriwilaijaroen N, Kelly JX et al. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob Agents Chemother 2004; 48: 1803-1806
• 30 R Development Core Team, R. A language and environment for statistical computing, R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-07-0, URL http://www.R-project.org 2011
• 31 Ritz C, Streibig JC. Bioassay analysis using RJ. Statist Software 12, 2005