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

• Autor(a) principal: Silva, Luiz Francisco Rocha e
• Data de Publicação: 2012
• Outros Autores: 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
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional do INPA
• Texto Completo: https://repositorio.inpa.gov.br/handle/1/16094
• topic: 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 Berghei; Plasmodium Falciparum; Quinolines; Murinae; Mus; Plasmodium Berghei; Plasmodium Falciparum

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.