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

Abstract

Neglected tropical diseases are one of the most important public health problems in many countries around the world. Among them are leishmaniasis, Chagas disease, and malaria, which contribute to more than 250 million infections worldwide. There is no validated vaccine to prevent these infections and the treatments available are obsolete, highly toxic, and non-effective due to parasitic drug resistance. Additionally, there is a high incidence of these diseases, and they may require hospitalization, which is expensive to the public health systems. Therefore, there is an urgent need to develop new treatments to improve the management of infected people, control the spread of resistant strains, and reduce health costs. Betulinic acid (BA) is a triterpene natural product which has shown antiparasitic activity against Leishmania, Trypanosoma cruzi, and Plasmodium. Here, we review the main results regarding the in vitro and in vivo pharmacological activity of BA and its derivatives against these parasites. Some chemical modifications of BA have been shown to improve its activities against the parasites. Further improvement on studies of drug-derived, as well as structure-activity relationship, are necessary for the development of new betulinic acid-based treatments.

Keywords: Chagas disease; betulinic acid; leishmaniasis; malaria; neglected tropical diseases; treatment.

Figure 2

BA and analogs may cause deformation in the lipid bilayer and, consequently, alterations in the erythrocyte shape. This mechanism of action results in the formation of echinocytes or stomatocytes structures ➀, and inhibits the Plasmodium invasion and growth ➁. The black X symbol represents a blockage of Plasmodium maturation into erythrocytes. BA structure (CID 64971) was obtained from PubChem [81].

Figure 1

Known mechanisms of parasite activity against Leishmania and T. cruzi. Previous work showed that dihydrobetulinic acid inhibits the interaction between topoisomerases I and II with the parasite DNA, inducing DNA brake and an apoptotic-like death in promastigotes and amastigotes. Regarding T. cruzi, it was shown a direct effect of BA5 on plasma membrane integrity, the formation of numerous and atypical vacuoles within the cytoplasm of the parasite, dilatation of some Golgi cisternae, and appearance of profiles of endoplasmatic reticulum involving organelles accompanied by the formation of autophagosomes, which ultimately result in trypomastigote cell death by necrosis. BA5 also reduced M1 markers and upregulated the M2 markers, inducing a regulatory phenotype.

Figure 3

Chemical structures of the main efficacious BA and BA-derivative compounds which presented activity against Leishmania, T. cruzi, and Plasmodium in previous studies. BA structure (CID 64971) was obtained from PubChem [81].