Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog

Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falc...

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Bibliographic Details
Authors: Silva, Luiz Francisco Rocha e, Montoia, Andréia, Amorim, Rodrigo C.N., Melo, Márcia R.S., Henrique, Marycleuma Campos, Nunomura, Sergio Massayoshi, Costa, Mônica Regina Farias, Andrade Neto, Valter Ferreira de, Costa, David Siqueira, Dantas, Glucia L.S., Lavrado, João, Moreira, Rui R.N., Paulo, Alexandra, Pinto, A. C., Tadei, Wanderli Pedro, Zacardi, R. S., Eberlin, M. N., Pohlit, Adrian Martin
Format: article
Status:Published version
Publication Date:2012
Country:Brasil
Institution:Instituto Nacional de Pesquisas da Amazônia (INPA)
Repository:Repositório Institucional do INPA
Language:English
OAI Identifier:oai:repositorio:1/16094
Online Access:https://repositorio.inpa.gov.br/handle/1/16094
Access Level:Open access
Keyword:Cryptolepine Derivative
Cryptolepine Triflate
Ellipticine
Olivacine
Unclassified Drug
Animals Experiment
Antimalarial Activity
Controlled Study
Drug Cytotoxicity
Ic 50
In Vitro Study
In Vivo Study
Lethal Dose
Mouse
Nonhuman
Plasmodium
Plasmodium Berghei
Priority Journal
Survival Time
Animal
Antimalarials
Aspidosperma
Ellipticines
Female
Indole Alkaloids
Macrophages
Malaria
Mice
Mice, Inbred Strains
Phytotherapy
Plant Extracts
Plasmodium Falciparum
Quinolines
Murinae
Mus
Description
Summary:Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC50 ≤ 1.4 μM, order of activity: 2b > 1 > 2a > 3). In vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (SI) of 10-12 for 2a and SI > 2.8 × 102 for 1, 2b and 3. 1 administered orally at 50 mg/kg/day was highly active against P. berghei (in vivo inhibition compared to untreated control (IVI) = 100%, mean survival time (MST) > 40 days, comparable activity to chloroquine control). 1 administered orally and subcutaneously was active at 10 mg/kg/day (IVI = 70-77%; MST = 27-29 days). 3 exhibited high oral activity at ≥50 mg/kg/day (IVI = 90-97%, MST = 23-27 days). Cryptolepine (2a) administered orally and subcutaneously exhibited moderate activity at 50 mg/kg/day (IVI = 43-63%, MST = 24-25 days). At 50 mg/kg/day, 2b administered subcutaneously was lethal to infected mice (MST = 3 days) and moderately active when administered orally (IVI = 45-55%, MST = 25 days). 1 and 3 are promising compounds for development of antimalarials. © 2012 Elsevier GmbH.

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