Recent Advances in the Chemistry and Pharmacology of Cryptolepine
191
8.4 Trypanosomiasis
Species of Trypanosoma are responsible for Human African Trypanosomiasis (HAT)
as well as Chagas’ disease in South America. The currently available antitrypanosomal drugs are of limited effectiveness, are often toxic to patients, and parasite
resistance is widespread [52]. Cryptolepine (1) and eight synthetic analogs have
been assessed for in vitro activity against T. brucei (strain 427) trypanosomes [52].
All these compounds displayed marked activity, with IC 50 values <1 nM, while 7bromo-, 2,7-dibromo- (43), 2-chloro- and 8-chloro-cryptolepine were active at <10
nM, with selectivity indices with respect to cytotoxicity for MAC 15a cells of >2000.
Three analogs (7-bromo-, 2, 7-dibromo- (43), and 8-chloro-cryptolepine) were then
assessed for in vivo activity in rats infected with T. brucei brucei (Lafia strain), and
when parasitemia was established the animals received a single dose of 20 mg/kg
by i.m. or i.v. injection or orally. Parasitemia and animal survival were monitored
daily. The most active compound was 43, which suppressed parasitemia when given
i.m., i.v., or orally, and increased survival times to 13 days in each case compared
to untreated infected animals that survived for only 8 days. Cryptolepine (1) (i.m.)
suppressed parasitemia transiently and survival was increased by only 1–2 days.
These results suggest that, as with malaria, 43 is a promising lead compound toward
new antitrypanosomal agents for the treatment of sleeping sickness, although its
potential against T. cruzi, the causative agent of Chagas’ disease, has not yet been
investigated. However, 1 has been identified in silico as a potential inhibitor of T.
cruzi trypanothione reductase, a key enzyme in the metabolism of Trypanosoma spp.
[53].
Alkylamine derivatives of 1 have also been shown to have potent and selective in vitro antitrypanosomal activity against T. brucei brucei and are also potent
inhibitors of T. cruzi papain-like cysteine proteases [54]. Quantitative structure–
activity relationships modeling studies of antitrypanosomal activities of alkyldiamine
cryptolepine derivatives have shown a good correlation between experimental and
predicted inhibitory values against T. cruzi and T. brucei rhodesiense cysteine
proteases. This strengthens the suggestion that inhibition of these enzymes explains,
at least in part, the potent activity of these compounds [55]. It is possible that the action
of 43 could involve cysteine protease inhibition and this mechanism might explain
(in part) the potent antiplasmodial activity of this compound as blood-stage Plasmodia spp. utilize proteases for the digestion of hemoglobin, representing a possible
second mechanism of action in addition to the inhibition of hemozoin formation (see
Section 8.3.2).
191
8.4 Trypanosomiasis
Species of Trypanosoma are responsible for Human African Trypanosomiasis (HAT)
as well as Chagas’ disease in South America. The currently available antitrypanosomal drugs are of limited effectiveness, are often toxic to patients, and parasite
resistance is widespread [52]. Cryptolepine (1) and eight synthetic analogs have
been assessed for in vitro activity against T. brucei (strain 427) trypanosomes [52].
All these compounds displayed marked activity, with IC 50 values <1 nM, while 7bromo-, 2,7-dibromo- (43), 2-chloro- and 8-chloro-cryptolepine were active at <10
nM, with selectivity indices with respect to cytotoxicity for MAC 15a cells of >2000.
Three analogs (7-bromo-, 2, 7-dibromo- (43), and 8-chloro-cryptolepine) were then
assessed for in vivo activity in rats infected with T. brucei brucei (Lafia strain), and
when parasitemia was established the animals received a single dose of 20 mg/kg
by i.m. or i.v. injection or orally. Parasitemia and animal survival were monitored
daily. The most active compound was 43, which suppressed parasitemia when given
i.m., i.v., or orally, and increased survival times to 13 days in each case compared
to untreated infected animals that survived for only 8 days. Cryptolepine (1) (i.m.)
suppressed parasitemia transiently and survival was increased by only 1–2 days.
These results suggest that, as with malaria, 43 is a promising lead compound toward
new antitrypanosomal agents for the treatment of sleeping sickness, although its
potential against T. cruzi, the causative agent of Chagas’ disease, has not yet been
investigated. However, 1 has been identified in silico as a potential inhibitor of T.
cruzi trypanothione reductase, a key enzyme in the metabolism of Trypanosoma spp.
[53].
Alkylamine derivatives of 1 have also been shown to have potent and selective in vitro antitrypanosomal activity against T. brucei brucei and are also potent
inhibitors of T. cruzi papain-like cysteine proteases [54]. Quantitative structure–
activity relationships modeling studies of antitrypanosomal activities of alkyldiamine
cryptolepine derivatives have shown a good correlation between experimental and
predicted inhibitory values against T. cruzi and T. brucei rhodesiense cysteine
proteases. This strengthens the suggestion that inhibition of these enzymes explains,
at least in part, the potent activity of these compounds [55]. It is possible that the action
of 43 could involve cysteine protease inhibition and this mechanism might explain
(in part) the potent antiplasmodial activity of this compound as blood-stage Plasmodia spp. utilize proteases for the digestion of hemoglobin, representing a possible
second mechanism of action in addition to the inhibition of hemozoin formation (see
Section 8.3.2).