2. 4.2 New generation of antimalarial drugs:
trioxaquines
As recommended by the WHO, the combination of at least two
drugs having different modes of action must be used to prevent the development
of drug resistance. Dechy et al. therefore adopted a covalent bitherapy
strategy by preparing new molecules named trioxaquines by covalently attaching
a trioxane, the moiety responsible for the activity of artemisinin, to a
4-aminoquinoline entity, a key constituent of chloroquine (Dechy- Cabaret,
2000; Rodriguez et al., 2003). DU-1102, the first trioxaquine proved very
active in vitro on chloroquine-sensitive and chloroquine-resistant
Plasmodium falciparum, both on laboratory strains (Dechy-Cabaret,
2000) and on human isolates. DU-1102 is a modular molecule that can be prepared
through a convergent synthesis from the cis-bicyclo [3.3.0] octane-3, 7-dione
in place of the 1,4-cyclohexanedione used to prepare DU-1102 (Dechy-Cabaret et
al., 2002) as shown in scheme 2-3.
Scheme 2-3.
Convergent synthesis of the trioxaquine, represented by the molecule
4.
2.2.4 Vaccine
Over the years, researchers confronting the extraordinarily
complex parasite have suffered a string of disappointments interspersed with
some high-profile setbacks, as promising candidate vaccines have failed to
perform up to expectations. The scientific obstacles are enormous: Compared to
a virus, with its dozen or so genes and relatively monomaniacal approach to
evading the human immune system, the malaria parasite has 14 chromosomes,
perhaps 7000 genes, and a four-stage life cycle as it passes from humans to
mosquitoes and back again. The existing different species of parasites and
their multistage life are obstacles for efficiency elaboration of vaccine.
Moreover, dozens of new vaccines are in the works, employing a host of
technologies that promise to attack the parasite at every vulnerable point of
its multistage life. Researchers now predict that within 5 or 10 years they
will have a successful vaccine that will actually save lives (Taubes, 2000).
2.2.5 Genetic approaches
With the actual human, related plasmodium species and mosquito
genome sequences, researchers now have in hand the genetic blueprints for the
parasite, its vector, and its victim. This will provide the ability to take a
holistic approach in understanding how the parasite interacts with the human
host. With that approach, new antimalarial strategies should be
possible (Pennisi, 2000). Transgenic mosquitoes could be one
product of these studies.
The goal would be to replace the natural mosquito populations
ravaging developing countries by "designer mosquitoes," genetically modified so
that they are unable to transmit malaria parasite. The development of this
technique is crucial for scientists studying the biology of the mosquito and
its interactions with the malaria-causing parasite. Genetic modification of
mosquitoes offers exciting possibilities for controlling malaria, but success
will depend on how transformation affects the fitness of modified
insects (Enserink, 2002; Flaminia et al., 2003).
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