Effect of synthetic betulinic acid derivatives on mitochondrial membrane potential (ΔΨm) in Plasmodium falciparum strains

Malaria is caused by a protozoan parasite, and the most virulent agent in humans is P. falciparum. Since the energy metabolism of Plasmodium is quite different from that of the mammalian host, the energy-transducing enzymes of the parasite are promising anti-malarial drug targets. Furthermore, due the importance of the Plasmodium mitochondria to many physiological activities, such as the metabolism of molecules and Ca²⁺ homeostasis, it has been validated as a drug target. In this work, we obtained betulinic acid (BA), a triterpene, from barks of Platanus acerifolia, and the modification at C-3 resulted in ten compounds. These derivatives were evaluated against the chloroquine-sensitive strain (3D7) of P. falciparum. The action mechanism of the derivatives 1 (IC₅₀ 4µM) and 2 (IC₅₀ 8µM) was investigated through the evaluation of ΔΨm using a technique described by Srivastava et al (1997). Only 1 had a collapse in ΔΨm at IC₅₀ 2 mM and showed a displacement histogram indicating the dissipation of ΔΨm. Our data showed that BA derivatives can be used as agents against the malaria protozoan, and the investigation of the action mechanism of these compounds can support the design and development of more potent derivatives.