Evaluation of Cryptolepine and Huperzine Derivatives as Lead Compounds towards New Agents for the Treatment of Human African Trypanosomiasis

Abstract

The alkaloid cryptolepine (1) and eight synthetic analogues (2-8) were assessed for in vitro activities against Trypanosoma brucei. Four of the analogues were found to be highly potent with IC 50 values of less than 3 nM and three of these were assessed against T. brucei brucei infection in rats. The most effective compound was 2, 7-dibromocryptolepine (7); a single oral dose of 20 mg/kg suppressed parasitaemia and increased the mean survival time to 13.6 days compared with 8.4 days for untreated controls. In addition, four huperzine derivatives (9-12) were shown to have in vitro antitrypanosomal activities with IC 50 values ranging from 303-377 nM.

Antileishmanial activity of cryptolepine analogues and apoptotic effects of 2,7-dibromocryptolepine against Leishmania donovani promastigotes

“…Previously, a substantial augmentation in the activity of the analogue 8 against Plasmodium falciparum and T. b. brucei (Wright et al 2001;Oluwafemi et al 2009) has been reported. Presently, we have observed a dramatic increase in antileishmanial potential of 8, with bromo-substituents at both 2 and 7 positions, in comparison to either the 2-bromo-(3), or the 7-bromo-(4) analogues.…”

“…Several halogenated derivatives of 1 were found to be considerably more potent than 1 and exhibited promising in vivo activity against Plasmodium berghei, the rodent malaria parasite (Onyeibor et al 2005). Again, the analogues like 2-chlorocryptolepine (5), 8-chlorocryptolepine (6), 7-bromocryptolepine (4), and 2, 7-dibromocryptolepine (8), have also been shown to be active against Trypanosoma brucei brucei, the causative parasite for African sleeping sickness (Oluwafemi et al 2009). Hence, it was considered worthwhile to investigate some of the cryptolepine analogues vis-à-vis cryptolepine against L. donovani, the related parasite causing visceral leishmaniasis.…”

Indoloquinolines as Scaffolds for Drug Discovery

“…In infected mice with P. berghei, the 2-chloro-7-bromo (30k) suppressed parasitemia by 90% at doses of 25 mg.kg -1 .day -1 , with no apparent toxicity to the mice. Like previously, the authors hypothesized that the mechanism of action of these compounds could be by inhibition of hemozoin formation in the food vacuole, however, no correlation between antiplasmodial activity and accumulation in the acid food vacuole, determined by a mathematical equation based on compounds pK a , was seen, suggesting that the antimalarial activity involves other mechanisms in addition to the inhibition of hemozoin formation [51,93]. Recently, Oluwafemi and coworkers evaluated the activity of 29n-t against T. brucei and four analogues were found to be highly potent (29o-q,s) when compared with 1 (IC 50 = 306 nM) [93].…”

Synthesis and biological evaluation of N -cyanoalkyl-, N -aminoalkyl-, and N -guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

“…We recently reported that huprine Y ( 1 , Fig. 1), a 7-chloro-4-aminoquinoline derivative with potent acetylcholinesterase (AChE) inhibitory activity, developed in our group as an anti-Alzheimer drug candidate, 28 exhibited significant activity against T. brucei (IC 50  = 0.61 μM, selectivity index (SI) over rat myoblast L6 cells = 13) 29, 30. In 4-aminoquinoline-based antimalarials, both dimerization and side chain modification have been used to increase potency and overcome parasite resistance 31, 32, 33, 34, 35.…”