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 inPlasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC50 <= 1.4 mu M, 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 x 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. (C) 2012 Elsevier GmbH. All rights reserved.