Ursolic and betulinic semisynthetic derivatives show activity against CQ‐resistant Plasmodium falciparum isolated from Amazonia

Abstract

ACT’s low levels of Plasmodium parasitemia clearance are worrisome since it is the last treatment option against P. falciparum. This scenario has led to investigations of compounds with different mechanisms of action for malaria treatment. Natural compounds like ursolic acid (UA) and betulinic acid (BA), distinguished by their activity against numerous microorganisms, including P. falciparum, have become relevant. This study evaluated the antiplasmodial activity of imidazole derivatives of UA and BA against P. falciparum in vitro. Eight molecules were obtained by semisynthesis and tested against P. falciparum strains (NF54 and CQ‐resistant 106/cand isolated in Porto Velho, Brazil); 2a and 2b showed activity against NF54 and 106/cand strains with IC50 < 10 µM. They presented high selectivity indexes (SI > 25) and showed synergism when combined with artemisinin. 2b inhibited the parasite's ring and schizont forms regardless of when the treatment began. In silico analysis presented a tight bind of 2b in the topoisomerase II‐DNA complex. This study demonstrates the importance of natural derivate compounds as new candidates for malarial treatment with new mechanisms of action. Semisynthesis led to new triterpenes that are active against P. falciparum and may represent new alternatives for malaria drug development.

Potential of Triterpenic Natural Compound Betulinic Acid for Neglected Tropical Diseases New Treatments

“…The molecular action mechanisms were also investigated in BA and derivatives against P. falciparum strains. Medeiros and collaborators [80] evaluated the in vitro antiplasmodial activity of imidazole derivatives of BA against P. falciparum NF54 and chloroquine-resistant isolated strains and observed that both derivatives presented good IC 50s values below 10 µM for both strains. In addition, the BA derivative with ester addition of butyric acid at C-3 also showed maturation inhibition of the parasite's ring to schizont forms when compared to the start of the treatment, potentiating the antimalarial effect in inhibiting the parasite life cycle.…”