Derivatives of Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Hepatic Stage of <i>Plasmodium berghei</i> Infection In Vitro
Kateřina Hradiská Breiterová,
Aneta Ritomská,
Diana Fontinha,
Jana Křoustková,
Daniela Suchánková,
Anna Hošťálková,
Marcela Šafratová,
Eliška Kohelová,
Rozálie Peřinová,
Rudolf Vrabec,
Denise Francisco,
Miguel Prudêncio,
Lucie Cahlíková
Affiliations
Kateřina Hradiská Breiterová
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
Aneta Ritomská
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
Diana Fontinha
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
Jana Křoustková
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
Daniela Suchánková
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
Anna Hošťálková
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
Marcela Šafratová
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
Eliška Kohelová
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
Rozálie Peřinová
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
Rudolf Vrabec
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
Denise Francisco
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
Miguel Prudêncio
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
Lucie Cahlíková
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
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.