Recent Advances in the Chemistry and Pharmacology of Cryptolepine
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8 Cryptolepine as a Lead to New Antiprotozoal Agents
8.1 Amebiasis
Aqueous and 80% methanol extracts of C. sanguinolenta root bark as well as cryptolepine (1) and neocryptolepine (2) were found to be active against Entamoeba
histolytica in vitro (IC 50 = 3.27 and 2.07 μM for 1 and 2, respectively). However,
these activities were 10-fold less than that of metronidazole (IC 50 = 0.2 μg/cm
3 ),
while quinoline and the dimeric alkaloids biscryptolepine and cryptoquindoline were
less active [29]. The aqueous extract was assessed for acute (single oral dose up to 5
g) and sub-acute (up to 800 mg/kg daily for 28 days) toxicity tests in rats; no significant toxic effects were observed. These findings lend some support to the traditional
use of C. sanguinolenta in the treatment of amebiasis.
8.2 Leishmaniasis
New drugs are urgently required for the treatment of visceral leishmaniasis, a parasitic
disease affecting the spleen and other internal organs caused by Leishmania donovani
[30]. Cryptolepine (1) was found to have moderate activity against L. donovani AG83
promastigotes (IC 50 = 8.2 μM, 12 h incubation) [31]. Further studies have indicated
that inhibition of autophagy is involved in cryptolepine-induced cell death, although
it should be noted that this work was carried out on the insect (promastigote) stage
of the parasite so may not be applicable to the human amastigote form. In another
study, 1 and 11 synthetic analogs of 1 were also tested against L. donovani AG83
promastigotes [32]. The most active compound was 2,7-dibromocryptolepine (43)
(IC 50 = 0.5 and 1.6 μM for 43 and 1, respectively). Compound 43 was also tested
against two clinical isolates of amastigotes cultured in mouse macrophage cells, of
which one was resistant to sodium stibogluconate. The resistant isolate was more
sensitive to 43 (IC 50 = > 5.0 and 3.4 μM against the sensitive and resistant parasites,
respectively), while the IC 50 value of 43 against mouse macrophages was 9.7 μM,
indicating some selective toxicity against the amastigote form.
8.3 Malaria
8.3.1 Ethnopharmacology
In 2018, malaria was responsible for an estimated 405,000 deaths of which 94%
occurred in Africa and 67% of global deaths were in children under the age of
five years [33]. Although the global incidence of malaria declined significantly from
187
8 Cryptolepine as a Lead to New Antiprotozoal Agents
8.1 Amebiasis
Aqueous and 80% methanol extracts of C. sanguinolenta root bark as well as cryptolepine (1) and neocryptolepine (2) were found to be active against Entamoeba
histolytica in vitro (IC 50 = 3.27 and 2.07 μM for 1 and 2, respectively). However,
these activities were 10-fold less than that of metronidazole (IC 50 = 0.2 μg/cm
3 ),
while quinoline and the dimeric alkaloids biscryptolepine and cryptoquindoline were
less active [29]. The aqueous extract was assessed for acute (single oral dose up to 5
g) and sub-acute (up to 800 mg/kg daily for 28 days) toxicity tests in rats; no significant toxic effects were observed. These findings lend some support to the traditional
use of C. sanguinolenta in the treatment of amebiasis.
8.2 Leishmaniasis
New drugs are urgently required for the treatment of visceral leishmaniasis, a parasitic
disease affecting the spleen and other internal organs caused by Leishmania donovani
[30]. Cryptolepine (1) was found to have moderate activity against L. donovani AG83
promastigotes (IC 50 = 8.2 μM, 12 h incubation) [31]. Further studies have indicated
that inhibition of autophagy is involved in cryptolepine-induced cell death, although
it should be noted that this work was carried out on the insect (promastigote) stage
of the parasite so may not be applicable to the human amastigote form. In another
study, 1 and 11 synthetic analogs of 1 were also tested against L. donovani AG83
promastigotes [32]. The most active compound was 2,7-dibromocryptolepine (43)
(IC 50 = 0.5 and 1.6 μM for 43 and 1, respectively). Compound 43 was also tested
against two clinical isolates of amastigotes cultured in mouse macrophage cells, of
which one was resistant to sodium stibogluconate. The resistant isolate was more
sensitive to 43 (IC 50 = > 5.0 and 3.4 μM against the sensitive and resistant parasites,
respectively), while the IC 50 value of 43 against mouse macrophages was 9.7 μM,
indicating some selective toxicity against the amastigote form.
8.3 Malaria
8.3.1 Ethnopharmacology
In 2018, malaria was responsible for an estimated 405,000 deaths of which 94%
occurred in Africa and 67% of global deaths were in children under the age of
five years [33]. Although the global incidence of malaria declined significantly from