The incidence rate of malaria and the ensuing mortality prompts the development of novel antimalarial drugs. In this work, the activity of twenty-eight Amaryllidaceae alkaloids (1-28) belonging to seven different structural types was assessed, as well as twenty semisynthetic derivatives of the β-crinane alkaloid ambelline (28a-28t) and eleven derivatives of the α-crinane alkaloid haemanthamine (29a-29k) against the hepatic stage of Plasmodium infection. Six of these derivatives (28h, 28m, 28n and 28r-28t) were newly synthesized and structurally identified. The most active compounds, 11-O-(3,5-dimethoxybenzoyl)ambelline (28m) and 11-O-(3,4,5-trimethoxybenzoyl)ambelline (28n), displayed IC50 values in the nanomolar range of 48 and 47 nM, respectively. Strikingly, the derivatives of haemanthamine (29) with analogous substituents did not display any significant activity, even though their structures are quite similar. Interestingly, all active derivatives were strictly selective against the hepatic stage of infection, as they did not demonstrate any activity against the blood stage of Plasmodium infection. As the hepatic stage is a bottleneck of the plasmodial infection, liver-selective compounds can be considered crucial for further development of the malaria prophylactics.

Prudêncio Lab Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina Universidade de Lisboa Av Prof Egas Moniz Edf Egas Moniz 1649 028 Lisboa Portugal

Secondary Metabolites of Plants as Potential Drugs Research Group Department of Pharmacognosy and Pharmaceutical Botany Faculty of Pharmacy Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

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World Health Organization . World Malaria Report 2021. World Health Organization; Geneva, Switzerland: 2021.

Suh K.N., Kain K.C., Keystone J.S. Malaria. Can. Med. Assoc. J. 2004;170:1693–1702. doi: 10.1503/cmaj.1030418. PubMed DOI PMC

Snow R.W., Guerra C.A., Noor A.M., Myint H.Y., Hay S.I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature. 2005;434:214–217. doi: 10.1038/nature03342. PubMed DOI PMC

Thu A.M., Phyo A.P., Landier J., Parker D.M., Nosten F.H. Combating multidrug-resistant Plasmodium falciparum malaria. FEBS J. 2017;284:2569–2578. doi: 10.1111/febs.14127. PubMed DOI PMC

Perkins S.L. Malaria’s many mates: Past, present, and future of the systematics of the order Haemosporida. J. Parasitol. 2014;100:11–25. doi: 10.1645/13-362.1. PubMed DOI

Ashley E.A., Pyae Phyo A., Woodrow C.J. Malaria. Lancet. 2018;391:1608–1621. doi: 10.1016/S0140-6736(18)30324-6. PubMed DOI

Agop-Nersesian C., Niklaus L., Wacker R., Heussler V.T. Host cell cytosolic immune response during Plasmodium liver stage development. FEMS Microbiol. Rev. 2018;42:324–334. doi: 10.1093/femsre/fuy007. PubMed DOI PMC

Kumar S., Bhardwaj T.R., Prasad D.N., Singh R.K. Drug targets for resistant malaria: Historic to future perspectives. Biomed. Pharmacother. 2018;104:8–27. doi: 10.1016/j.biopha.2018.05.009. PubMed DOI

Frevert U. Sneaking in through the back entrance: The biology of malaria liver stages. Trends Parasitol. 2004;20:417–424. doi: 10.1016/j.pt.2004.07.007. PubMed DOI

Fontinha D., Moules I., Prudêncio M. Repurposing drugs to fight hepatic malaria parasites. Molecules. 2020;25:3409. doi: 10.3390/molecules25153409. PubMed DOI PMC

Cowman A.F., Healer J., Marapana D., Marsh K. Malaria: Biology and disease. Cell. 2016;167:610–624. doi: 10.1016/j.cell.2016.07.055. PubMed DOI

Rodrigues T., Prudêncio M., Moreira R., Mota M.M., Lopes F. Targeting the liver stage of malaria parasites: A yet unmet goal. J. Med. Chem. 2012;55:995–1012. doi: 10.1021/jm201095h. PubMed DOI

Mota M.M., Rodriguez A. New pieces for the malaria liver stage puzzle: Where will they fit? Cell Host Microbe. 2008;3:63–65. doi: 10.1016/j.chom.2008.01.004. PubMed DOI

Alam A., Goyal M., Iqbal M.S., Pal C., Dey S., Bindu S., Maity P., Bandyopadhyay U. Novel antimalarial drug targets: Hope for new antimalarial drugs. Expert Rev. Clin. Pharmacol. 2009;2:469–489. doi: 10.1586/ecp.09.28. PubMed DOI

Daily J. Malaria 2017: Update on the clinical literature and management. Curr. Infect. Dis. Rep. 2017;19:28. doi: 10.1007/s11908-017-0583-8. PubMed DOI

Uthman O.A., Graves P.M., Saunders R., Gelband H., Richardson M., Garner P. Safety of primaquine given to people with G6PD deficiency: Systematic review of prospective studies. Malar. J. 2017;16:346. doi: 10.1186/s12936-017-1989-3. PubMed DOI PMC

Dean L., Kane M. Tafenoquine therapy and G6PD genotype. In: Pratt V.M., Scott S.A., Pirmohamed M., editors. Medical Genetics Summaries. National Center for Biotechnology Information; Bethesda, ML, USA: 2012. PubMed

Kappe S.H., Duffy P.E. Malaria liver stage culture: In Vitro veritas? Am. J. Trop. Med. Hyg. 2006;74:706–707. doi: 10.4269/ajtmh.2006.74.706. PubMed DOI

Antony H.A., Parija S.C. Antimalarial drug resistance: An overview. Trop. Parasitol. 2016;6:30–41. doi: 10.4103/2229-5070.175081. PubMed DOI PMC

Mvumbi D.M., Bobanga T.L., Kayembe J.-M.N., Mvumbi G.L., Situakibanza H.N.-T., Benoit-Vical F., Melin P., De Mol P., Hayette M.-P. Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo. PLoS ONE. 2017;12:e0179142. doi: 10.1371/journal.pone.0179142. PubMed DOI PMC

Septembre-Malaterre A., Lalarizo Rakoto M., Marodon C., Bedoui Y., Nakab J., Simon E., Hoarau L., Savriama S., Strasberg D., Guiraud P., et al. Artemisia annua, a traditional plant brought to light. Int. J. Mol. Sci. 2020;21:4986. doi: 10.3390/ijms21144986. PubMed DOI PMC

Ariey F., Witkowski B., Amaratunga C., Beghain J., Langlois A.-C., Khim N., Kim S., Duru V., Bouchier C., Ma L., et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50–55. doi: 10.1038/nature12876. PubMed DOI PMC

Nosten F., White N.J. Artemisinin-based combination treatment of falciparum malaria. Am. J. Trop. Med. Hyg. 2007;77:181–192. doi: 10.4269/ajtmh.2007.77.181. PubMed DOI

Pazhayam N.M., Chhibber-Goel J., Sharma A. New leads for drug repurposing against malaria. Drug Discov. Today. 2019;24:263–271. doi: 10.1016/j.drudis.2018.08.006. PubMed DOI

Kaiser M., Mäser P., Tadoori L.P., Ioset J.R., Brun R. Antiprotozoal activity profiling of approved drugs: A starting point toward drug repositioning. PLoS ONE. 2015;10:e0135556. doi: 10.1371/journal.pone.0135556. PubMed DOI PMC

Newman D.J., Cragg G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 2020;83:770–803. doi: 10.1021/acs.jnatprod.9b01285. PubMed DOI

Nyunt M.M., Nguyen V.K., Kajubi R., Huang L., Ssebuliba J., Kiconco S., Mwima M.W., Achan J., Aweeka F., Parikh S., et al. Artemether-lumefantrine pharmacokinetics and clinical response are minimally altered in pregnant ugandan women treated for uncomplicated falciparum malaria. Antimicrob. Agents Chemother. 2015;60:1274–1282. doi: 10.1128/AAC.01605-15. PubMed DOI PMC

World Flora Online. [(accessed on 10 November 2022)]. Available online: http://worldfloraonline.org/taxon/wfo-7000000018#feedbackModal.

Berkov S., Osorio E., Viladomat F., Bastida J. The Alkaloids. 1st ed. Volume 83. Elsevier Inc.; Amsterdam, The Netherlands: 2020. Chemodiversity, chemotaxonomy and chemoecology of Amaryllidaceae alkaloids; pp. 113–185. PubMed DOI

Nair J., van Staden J. Antiplasmodial studies within the plant family Amaryllidaceae. Nat. Prod. Commun. 2019;14:1934578X1987293. doi: 10.1177/1934578X19872931. DOI

Soto-Vásquez M.R., Horna-Pinedo M.V., Tallini L.R., Bastida J. Chemical composition and in vitro antiplasmodial activity of the total alkaloids of the bulbs of two Amaryllidaceae species from northern Peru. Pharmacogn. J. 2021;13:1046–1052. doi: 10.5530/pj.2021.13.135. DOI

Cahlíková L., Kawano I., Řezáčová M., Blunden G., Hulcová D., Havelek R. The Amaryllidaceae alkaloids haemanthamine, haemanthidine and their semisynthetic derivatives as potential drugs. Phytochem. Rev. 2021;20:303–323. doi: 10.1007/s11101-020-09675-8. DOI

Gonring-Salarini K., Conti R., Andrade J.P., Borges B.J.P., Aguiar A.C., de Souza J.O., Zanini C.L., Oliva G., Tenorio J.C., Ellena J., et al. In vitro antiplasmodial activities of alkaloids isolated from roots of Worsleya procera (Lem.) Traub (Amaryllidaceae) J. Braz. Chem. Soc. 2019;30:1624–1633. doi: 10.21577/0103-5053.20190061. DOI

Cho N., Du Y., Valenciano A.L., Fernández-Murga M.L., Goetz M., Clement J., Cassera M.B., Kingston D.G.I. Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud. Bioorg. Med. Chem. Lett. 2018;28:40–42. doi: 10.1016/j.bmcl.2017.11.021. PubMed DOI PMC

Akinyele S.T., Elusiyan C.A., Omisore N.O., Adewunmi C.O. Antimalarial activities and alkaloids from Crinum jagus (Thomps) DANDY. J. Ethnopharmacol. 2022;296:115359. doi: 10.1016/j.jep.2022.115359. PubMed DOI

Tajuddeen N., Van Heerden F.R. Antiplasmodial natural products: An update. Malar. J. 2019;18:404. doi: 10.1186/s12936-019-3026-1. PubMed DOI PMC

Vaněčková N., Hošťálková A., Šafratová M., Kuneš J., Hulcová D., Hrabinová M., Doskočil I., Štěpánková Š., Opletal L., Nováková L., et al. Isolation of Amaryllidaceae alkaloids from Nerine bowdenii W. Watson and their biological activities. RSC Adv. 2016;6:80114–80120. doi: 10.1039/C6RA20205E. DOI

Šafratová M., Hošťálková A., Hulcová D., Breiterová K., Hrabcová V., Machado M., Fontinha D., Prudêncio M., Kuneš J., Chlebek J., et al. Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity. Arch. Pharm. Res. 2018;41:208–218. doi: 10.1007/s12272-017-1000-4. PubMed DOI

Hulcová D., Maříková J., Korábečný J., Hošťálková A., Jun D., Kuneš J., Chlebek J., Opletal L., De Simone A., Nováková L., et al. Amaryllidaceae alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master as potential drugs in treatment of Alzheimer’s disease. Phytochemistry. 2019;165:112055. doi: 10.1016/j.phytochem.2019.112055. PubMed DOI

Breiterová K., Koutová D., Maříková J., Havelek R., Kuneš J., Majorošová M., Opletal L., Hošťálková A., Jenčo J., Řezáčová M., et al. Amaryllidaceae alkaloids of different structural types from Narcissus L. cv. Professor Einstein and their cytotoxic activity. Plants. 2020;9:137. doi: 10.3390/plants9020137. PubMed DOI PMC

Maříková J., Ritomská A., Korábečný J., Peřinová R., Al Mamun A., Kučera T., Kohelová E., Hulcová D., Kobrlová T., Kuneš J., et al. Aromatic esters of the crinane amaryllidaceae alkaloid ambelline as selective inhibitors of butyrylcholinesterase. J. Nat. Prod. 2020;83:1359–1367. doi: 10.1021/acs.jnatprod.9b00561. PubMed DOI

Viladomat F., Codina C., Bastida J., Mathee S., Campbell W.E. Further alkaloids from Brunsvigia josephinae. Phytochemistry. 1995;40:961–965. doi: 10.1016/0031-9422(95)00375-H. DOI

Kohelová E., Peřinová R., Maafi N., Korábečný J., Hulcová D., Maříková J., Kučera T., Martínez González L., Hrabinová M., Vorčáková K., et al. Derivatives of the β-crinane amaryllidaceae alkaloid haemanthamine as multi-target directed ligands for alzheimer’s disease. Molecules. 2019;24:1307. doi: 10.3390/molecules24071307. PubMed DOI PMC

Peřinová R., Maafi N., Korábečný J., Kohelová E., De Simone A., Al Mamun A., Hulcová D., Marková J., Kučera T., Jun D., et al. Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer’s disease. Bioorg. Chem. 2020;100:103928. doi: 10.1016/j.bioorg.2020.103928. PubMed DOI

Prudêncio M., Mota M.M., Mendes A.M. A toolbox to study liver stage malaria. Trends Parasitol. 2011;27:565–574. doi: 10.1016/j.pt.2011.09.004. PubMed DOI

Ploemen I.H.J., Prudêncio M., Douradinha B.G., Ramesar J., Fonager J., van Gemert G.-J., Luty A.J.F., Hermsen C.C., Saurwein R.W., Baptista F.G., et al. Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging. PLoS ONE. 2009;4:e7881. doi: 10.1371/journal.pone.0007881. PubMed DOI PMC

Singh L., Fontinha D., Francisco D., Mendes A.M., Prudêncio M., Singh K. Molecular design and synthesis of ivermectin hybrids targeting hepatic and erythrocytic stages of Plasmodium parasites. J. Med. Chem. 2020;63:1750–1762. doi: 10.1021/acs.jmedchem.0c00033. PubMed DOI

Havelek R., Muthna D., Tomšík P., Královec K., Seifrtová M., Cahlíková L., Hošťálková A., Šafratová M., Perwein M., Čermáková E., et al. Anticancer potential of Amaryllidaceae alkaloids evaluated by screening with a panel of human cells, real-time cellular analysis and Ehrlich tumor-bearing mice. Chem. Biol. Interact. 2017;275:121–132. doi: 10.1016/j.cbi.2017.07.018. PubMed DOI