Malaria is responsible for more deaths around the world than any other parasitic
disease. Due to the emergence of strains that are resistant to the current
chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains
urgent though hampered by a lack of knowledge regarding the molecular mechanisms of
artemisinin resistance. Semisynthetic compounds derived from diterpenes from the
medicinal plant Wedelia paludosa were tested in silico against
the Plasmodium falciparum Ca2+-ATPase, PfATP6. This
protein was constructed by comparative modelling using the three-dimensional
structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best
docking scores, indicating a better interaction with PfATP6 than that of
thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds
could promote a change in calcium homeostasis, leading to parasite death. These data
suggest PfATP6 as a potential target for the antimalarial
ent-kaurane diterpenes.
The
need to develop new alternatives for antimalarial treatment
is urgent. Herein, we report the synthesis and antimalarial evaluation
of a small library of synthetic 3-alkylpyridine marine alkaloid (3-APA)
analogs. First, the compounds were evaluated in vitro against Plasmodium falciparum. The most active compound 5c was selected for optimization of its antimalarial properties.
An in silico approach was used based on pure ab initio electronic
structure prediction, and the results indicated that a substitution
of the hydroxyl group by a fluorine atom could favor a more stable
complex with heme at a molecular ratio of 2:1 (heme/3-APA halogenated).
A new fluorinated 3-APA analog was synthesized (compound 7), and its antimalarial activity was re-evaluated. Compound 7 exhibited optimized antimalarial properties (P. falciparum IC50 = 2.5 μM), low
genotoxicity, capacity to form a more stable heme/3-APA complex at
a molecular ratio of 2:1, and conformity to RO5. The new compound,
therefore, has great potential as a new lead antimalarial agent.
Introduction: Due to the emergence of resistance to antimalarial drugs as well as the lack of vaccination for malaria, there is an urgent demand for the development of new antimalarial alternatives. Recently, our research group developed a new set of 3-alkylpyridine marine alkaloid analogs, of which a compound known as compound 5 was found to be inactive against Plasmodium falciparum.Methods: Herein, we report a successful halogenation strategy to improve the antiplasmodial activity of compound 5 through the replacement of a hydroxyl group by chlorine (compound 6) and fluorine (compound 7) atoms. Results: Compounds 6 and 7 showed improved antiplasmodial activities (IC50 = 7.2 and 8.3 µM, respectively) 20 times higher than that of their precursor, compound 5 (IC50 = 210.7 µM). Ultraviolet-visible titration experiments demonstrated that halogenation of compound 5 did not alter its ability to bind its target, hematin. Conclusion: Halogenation can enhance the antiplasmodial activity of a compound without altering its mechanism of action.
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