Compostos multialvo contra doença de Chagas e doença do sono: uma revisão de literatura

Abstract

Neglected tropical diseases (NTDs) make up a set of pathologies, endemic in regions of socioeconomic vulnerability, including Chagas disease, caused by the parasite Trypanosoma cruzi, and sleeping sickness, caused by Trypanosoma brucei. One of the main problems related to NTDs is the lack of access to preventive measures for the diseases mentioned, as well as the lack of drug treatments for them. However, although there are few studies that seek to develop new medications for this purpose, it is possible to identify some therapeutic classes that have shown themselves to be promising and strategic in overcoming the aforementioned deficiency. After reviewing the literature, using virtual databases such as Bentham Science, MDPI and Science Direct, it was possible to observe some molecules with multi-target action against T. cruzi or T. brucei. In Chagas disease it was possible to observe this action of the compounds: nitrofurans, by inhibiting sterol synthesis and inducing oxidative stress; benzothioureas, by inhibiting cruzain and CYP51; chalcones, by also inhibiting cruzain, but in addition to the inhibition of trypanothione reductase; phenylpropanoids, by inhibiting protein kinases and inducing oxidative reactions; and finally the repositioning of Metrotexate, as it inhibited the enzymes Dihydrofolate reductase (DHFR) and Pteridine Reductase 1 (PTR1). Furthermore, it was possible to observe the inhibition of DHFR and PTR1, also in studies focused on T. brucei, through the action of sesquiterpene lactones, curcumin, Tb DHFR inhibitor cycloguanil (CYC), pyrimethamine (PYR) and alkaloids. However, other targets were inhibited or induced in T.brucei, such as the inhibition of phosphodiesterases 1 and 2 by the antineoplastic piclamilast; inhibition of protein kinases and induction of oxidative reactions by naphthoquinone and biphenyldiamidine, as well as the action of the compound 16-α-hydroxycleroda-3,13 (14)-Z-dien-15,16-olide, isolated from Polyalthia longifolia, which was capable of inducing the formation of oxygen radicals through more than one pathway. However, it was possible to highlight the inhibition of the enzymes DHFR and PTR1, as being the most promising multi-target action, considering that these enzymes are present in both T. cruzi and T. brucei, being responsible for the metabolism of folate, essential in parasitic development. Finally, the alkaloid (25) and Pyrimethamine proved to be strategic molecules, as they predominantly inhibited the PTR1 enzyme, present only in parasites, which is preferable as a therapeutic target.