Abstract
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.
Highlights
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
In Brazil, the number of malaria cases increased by 48% in 2017 compared to 2016.2 Malaria in humans is caused by different Plasmodium species: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale
The hydroxyl group of compound 5 was substituted by a chlorine and a fluorine atom using N-chlorosuccinimide and Diethylamino sulfur trifluoride (DAST) to afford compounds 6 and 7, respectively
Summary
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. 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. Conclusion: Halogenation can enhance the antiplasmodial activity of a compound without altering its mechanism of action. An estimated 435 thousand deaths globally were attributable to malaria, with children under 5 years of age accounting for 61% (266.000) of all deaths.[1] in Brazil, the number of malaria cases increased by 48% in 2017 compared to 2016.2 Malaria in humans is caused by different Plasmodium species: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale. The high rate of sequestration of P. falciparum-infected erythrocytes is a feature of severe P. falciparum infection.[4]
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