190
S. D. Shnyder and C. W. Wright
43 may have a significant advantage over drugs with a single mode of action with
respect to resilience to parasite resistance and as a simpler, more economical therapy.
A number of other compounds based on 1 have been synthesized as potential
antimalarials. Since the antimalarial mode of action of 1 involves the inhibition
of hemozoin formation, it was suggested that structural modifications such as the
addition of another protonable nitrogen resulting in higher accumulation into the
parasite’s acidic food vacuole may be expected to result in more potent antiplasmodial
activity [10]. This hypothesis was tested with the synthesis of a series of analogs
incorporating alkyl diamine side chains at C-11, for example, 44, which showed
significantly increased activities against chloroquine-resistant P. falciparum in vitro,
when compared to the parent compound, and with improved cytotoxic/antiplasmodial
selectivity indices [47]. However, fluorescence microscopy of parasite-infected red
blood cells showed that these compounds accumulated into the parasite nucleus and
that most of the compounds were able to bind to double-stranded DNA as well as
to hematin, suggesting that both of these targets are involved in their antiplasmodial
action. Knowledge of protonatable sites in cryptolepine analogs is clearly important
for understanding their antiplasmodial action, and
1 H-NMR spectroscopy has been
employed to identify them and determine their dissociation constants [48]. In another
study, Behzadi et al. in 2011 explored the relationship between the antiplasmodial
activities of 2-bromo- and 2,7-dibromocryptolepine (43) and shielding tensors, which
may be relevant to the design of new analogs [49]. The possibility remains that
cryptolepine analogs incorporating basic groups but which are unable to intercalate
into DNA could be potentially interesting lead to antimalarial compounds.
In a series of indolo[3,2-b]-C11-carboxamides, 2-bromo-N-[2-(piperidin-1yl)ethyl]-10H-indolo[3,2b]quinoline-11-carboxamide (Fig. 11, 45) was the most
promising compound (IC 50 = 1.3 μM against P. falciparum in vitro) [50]. This
compound is interesting in that the nitrogen at N-5 is not quaternary as in cryptolepine, a feature considered important for antiplasmodial activity [40], and, in
addition to inhibiting hemozoin formation, it has been shown to inhibit malaria parasite hemoglobin uptake. However, although orally active with predicted favorable
pharmacokinetics, the suppression of parasitemia in mice infected with P. berghei
was no more than 35% when compared to untreated infected mice [50].
Further syntheses of novel cryptolepine analogs aimed at increasing antiplasmodial potency, optimizing pharmacokinetic properties and with activities against
liver and sexual stage malaria parasites would be worthwhile. However, from an
environmental perspective, organic synthesis is not generally eco-friendly and as the
majority of malaria patients are poor, the affordability of antimalarial drugs is an
important consideration. An alternative approach that has the potential to address
these issues could be to cultivate C. sanguinolenta and then extract 1 from the roots
as a precursor for the production of semi-synthetic analog leads for novel antimalarial
drugs. Recent work has resulted in the development of a simple and efficient alkaloid
extraction process using non-toxic environmentally friendly solvents for the isolation
of 1, and preliminary experiments have shown that 1 may be halogenated directly to
yield semi-synthetic analogs such as 46 with potent antiplasmodial activities [51].
S. D. Shnyder and C. W. Wright
43 may have a significant advantage over drugs with a single mode of action with
respect to resilience to parasite resistance and as a simpler, more economical therapy.
A number of other compounds based on 1 have been synthesized as potential
antimalarials. Since the antimalarial mode of action of 1 involves the inhibition
of hemozoin formation, it was suggested that structural modifications such as the
addition of another protonable nitrogen resulting in higher accumulation into the
parasite’s acidic food vacuole may be expected to result in more potent antiplasmodial
activity [10]. This hypothesis was tested with the synthesis of a series of analogs
incorporating alkyl diamine side chains at C-11, for example, 44, which showed
significantly increased activities against chloroquine-resistant P. falciparum in vitro,
when compared to the parent compound, and with improved cytotoxic/antiplasmodial
selectivity indices [47]. However, fluorescence microscopy of parasite-infected red
blood cells showed that these compounds accumulated into the parasite nucleus and
that most of the compounds were able to bind to double-stranded DNA as well as
to hematin, suggesting that both of these targets are involved in their antiplasmodial
action. Knowledge of protonatable sites in cryptolepine analogs is clearly important
for understanding their antiplasmodial action, and
1 H-NMR spectroscopy has been
employed to identify them and determine their dissociation constants [48]. In another
study, Behzadi et al. in 2011 explored the relationship between the antiplasmodial
activities of 2-bromo- and 2,7-dibromocryptolepine (43) and shielding tensors, which
may be relevant to the design of new analogs [49]. The possibility remains that
cryptolepine analogs incorporating basic groups but which are unable to intercalate
into DNA could be potentially interesting lead to antimalarial compounds.
In a series of indolo[3,2-b]-C11-carboxamides, 2-bromo-N-[2-(piperidin-1yl)ethyl]-10H-indolo[3,2b]quinoline-11-carboxamide (Fig. 11, 45) was the most
promising compound (IC 50 = 1.3 μM against P. falciparum in vitro) [50]. This
compound is interesting in that the nitrogen at N-5 is not quaternary as in cryptolepine, a feature considered important for antiplasmodial activity [40], and, in
addition to inhibiting hemozoin formation, it has been shown to inhibit malaria parasite hemoglobin uptake. However, although orally active with predicted favorable
pharmacokinetics, the suppression of parasitemia in mice infected with P. berghei
was no more than 35% when compared to untreated infected mice [50].
Further syntheses of novel cryptolepine analogs aimed at increasing antiplasmodial potency, optimizing pharmacokinetic properties and with activities against
liver and sexual stage malaria parasites would be worthwhile. However, from an
environmental perspective, organic synthesis is not generally eco-friendly and as the
majority of malaria patients are poor, the affordability of antimalarial drugs is an
important consideration. An alternative approach that has the potential to address
these issues could be to cultivate C. sanguinolenta and then extract 1 from the roots
as a precursor for the production of semi-synthetic analog leads for novel antimalarial
drugs. Recent work has resulted in the development of a simple and efficient alkaloid
extraction process using non-toxic environmentally friendly solvents for the isolation
of 1, and preliminary experiments have shown that 1 may be halogenated directly to
yield semi-synthetic analogs such as 46 with potent antiplasmodial activities [51].