title: Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog.
abstract: 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 50mg/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 50mg/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.
authors.affiliation: National Institute for Amazonian Research, Av. André Araújo 2936, Aleixo, 69060-001 Manaus, Amazonas, Brazil.
authors.forename: L F
authors.initials: LF
authors.lastname: Rocha e Silva
authors.forename: A
authors.initials: A
authors.lastname: Montoia
authors.forename: R C N
authors.initials: RC
authors.lastname: Amorim
authors.forename: M R
authors.initials: MR
authors.lastname: Melo
authors.forename: M C
authors.initials: MC
authors.lastname: Henrique
authors.forename: S M
authors.initials: SM
authors.lastname: Nunomura
authors.forename: M R F
authors.initials: MR
authors.lastname: Costa
authors.forename: V F
authors.initials: VF
authors.lastname: Andrade Neto
authors.forename: D S
authors.initials: DS
authors.lastname: Costa
authors.forename: G
authors.initials: G
authors.lastname: Dantas
authors.forename: J
authors.initials: J
authors.lastname: Lavrado
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.forename: A
authors.initials: A
authors.lastname: Paulo
authors.forename: A C
authors.initials: AC
authors.lastname: Pinto
authors.forename: W P
authors.initials: WP
authors.lastname: Tadei
authors.forename: R S
authors.initials: RS
authors.lastname: Zacardi
authors.forename: M N
authors.initials: MN
authors.lastname: Eberlin
authors.forename: A M
authors.initials: AM
authors.lastname: Pohlit
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D030009:Aspidosperma / Q000737:chemistry*; D004611:Ellipticines / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D026121:Indole Alkaloids / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008815:Mice, Inbred Strains; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D004611:Ellipticines; D026121:Indole Alkaloids; D010936:Plant Extracts; D011804:Quinolines; C034192:ellipticine; C024015:cryptolepine; C011521:olivacine