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Antimalarial and antileishmanial activity of novel 13-benzyl-15,16-bisnorlabdane derivatives

Posted on 20. December, 2013.

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Malaria and leishmaniasis are protozoan diseases with a high mortality rate affecting millions of people every year. Globally, an estimated 3.3 billion people were at risk of malaria in 2011, and estimates by the World Health Organization (WHO) have indicated that approximately 80% of cases and 90% of deaths occur in Africa, with children less than five years of age and pregnant women most severely affected. The Plasmodium falciparum parasite is responsible for most fatal cases of malaria. Leishmaniasis threatens about 350 million people in 98 countries or territories around the world, about 2 million estimated new cases occurring each year, and 12 million people are believed to be currently infected. The synthesis of 12 novel related-labdane-related natural products with antiparasitic activity is reported.

Malarial parasites have developed unacceptable levels of resistance towards existing treatment regimens3–8 and drugs currently used against leishmaniasis show high toxicities, producing clinical resistance and requiring longterm treatment.9 Therefore, there is an urgent need for a rapid search and discovery of new antimalarial and antileishmanial agents with a novel structural backbone. Plants have traditionally been an excellent and reliable source for the discovery and development of new drugs. Although several synthetic drugs possess structures with little resemblance to those of natural products, these compounds are often superior as therapeutic agents to their natural counterparts. However, half the drugs on the market are direct descendants of natural products.10 Labdanes diterpenoids are among the most common types of bicyclic diterpenes isolated from plants and sponges11–15 and they have shown a large spectrum of interesting biological activity such as cytotoxic, antifungal, anti-inflammatory, antiparasitic and analgesic activity.16 Several natural labdanetype diterpenes have shown good activity against chloroquine sensitive (compounds 1–6, IC50 = 24.0–54.0 μM) and resistant (compounds 8–13, IC50 = 5.0–39.9 μM) Plasmodium falciparum strain (3D7 and FcB1, respectively)17–19 and against Leishmania donovani (compounds 7, 14 and 15, IC50 = 5.7–60.0 μM).20,21. In this context, we previously reported the synthesis of optically active labdane-related natural products showing antimalarial activity, which act by inhibiting the β-hematin formation and/or the globin proteolysis. Some of them showed a significant inhibition of one process or a moderate inhibition of both.22 In continuation of this work, aimed at discovering compounds with antiparasitic activity, we report the preparation and, antimalarial and antileishmanial activity of 12 novel related-labdane 13-benzyl-15,16-bisnorlabdanes 21a–23d in which the C-13 and C-14 substituents are varied.

1.World Health Organization, World malaria report 2012, WHO Press, Switzerland, Geneva, 2012. pp. 88.
2.World Health Organization, Research priorities for Chagas disease, human African Trypanosomiasis and Leishmaniasis (technical report series, No. 975), WHO Press, Switzerland, Geneva, 2012. pp. 100.
3.World Health Organization, Global report on antimalarial drug efficacy and drug resistance: 2000–2010, WHO Press, Switzerland, Geneva, 2010. pp. 115.
4.U. Farooq and R.J. Mahajan, Vect. Borne. Dis., 2004, 41, 45.
5.C. Amaratunga, S. Sreng, S. Suon et al., Lancet Infect. Dis., 2012, 12, 851.
6.A.P. Phyo, S. Nkhoma, K. Stepniewska et al., The Lancet, 2012, 379, 1960.
7.Q. Cheng, D.E. Kyle and M.L. Gatton, Int. J. Parasitol. Drugs Drug Resist., 2012, 2, 249.
8.A.M. Dondorp, F. Nosten, P. Yi et al., N. Engl. J. Med., 2009, 361, 455.
9.H.W. Murray, Am. J. Trop. Med. Hyg., 2004, 71, 787.
10.D. Kinghorn, J.N. Pan and C.F. Heebyung, J. Nat. Prod., 2011, 74, 1539.
11.J.R. Hanson, Nat. Prod. Rep., 2012, 29, 890.
12.J.R. Hanson, Nat. Prod. Rep., 2011, 28, 1755.
13.J.R. Hanson, Nat. Prod. Rep., 2009, 26, 1156.
14.J.R. Hanson, Nat. Prod. Rep., 2007, 24, 1332.
15.I.S. Marcos, L. Castañeda, P. Basabe, D. Díez and J.G. Urones, Mini-Rev. Org. Chem., 2012, 9, 54.
16.I. Chinou, Curr. Med. Chem., 2005, 12, 1295.
17.G. Duker-Eshun, J.W. Jaroszewski, W.A. Asomaning et al., Planta Med.,2002, 68, 642.
18.J. Asili, M. Lambert, H.L. Ziegler et al., J. Nat. Prod., 2004, 67, 631.
19.M. Kenmogne, E. Prost, D. Harakat et al., Phytochemistry, 2006, 67, 433
20.Z. Cheikh-Ali, T. Okpekon, F. Roblot et al., Phytochemistry Lett., 2011, 4,240.
21.V. Samoylenko, D.C. Dunbar, M.A. Gafur et al., Phytother. Res., 2008, 22,1570
22.J.E. Villamizar, J.P. Pittelaud, J.R. Rodrigues et al., Nat. Prod. Res., 2009, 23, 891.

Read the article here, in the November issue of Journal of Chemical Research.


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