SÍNTESE E INVESTIGAÇÃO DO POTENCIAL FARMACOLÓGICO DE ANÁLOGOS FLAVONOIDICOS INIBIDORES DE CISTEÍNO PROTEASE PARA O TRATAMENTO DE LEISHMANIOSE CUTÂNEA

Abstract

Neglected tropical diseases (NTDs) encompass a diverse and extensive group of infectious diseases that can be caused by several etiological agents. NTDs particularly affect tropical continents such as Africa, Asia, and the Americas, and the most relevant epidemiological numbers are associated with social vulnerability. This group of diseases is estimated to represent a risk to approximately two billion people worldwide, with significant consequences for health, the economy. Among NTDs, the epidemiological numbers of leishmaniasis are particularly alarming in Brazil. This group of diseases can be caused by numerous species of the Leishmania parasite that are transmitted by the bite of infected females of phlebotomine sand flies. This form of transmission further aggravates the control of this group of diseases in Brazil, since sand flies are endemic in all regions of the country. Although considered a serious public health problem, the fight against leishmaniasis still suffers from the consequences of an old and expensive therapeutic treatment that cause several side effects. In this context, different drug discovery tools have been explored to allow the search for new efficient and low-cost prototypes. Among them, the use of multitarget compounds and inhibitors of parasite virulence factors stand out. Flavonoids represent a great source of bioactive compounds with these features; however, the low isolation yields of these compounds are obstacles for their clinical use. The present study aimed to synthesize flavonoid analogues with antileishmanial potential using simple, versatile, and low-cost methods. The compounds obtained were subjected to enzymatic inhibition tests against different isoforms of Leishmania cysteine proteases. In vitro assays demonstrated a relationship between enzymatic inhibition and the combat against parasite amastigotes by increasing nitric oxide production. Additionally, in silico studies allowed us to explore possible modes of interaction between the compounds and the enzyme, assisting the elaboration of a structure-activity relationship. Flow cytometry assays also demonstrated a depolarization of the Leishmania mitochondrial membrane after 48 h of treatment with the compounds, confirming the multitarget characteristic of the flavonoid derivatives. The molecules were also subjected to cytotoxicity tests that demonstrated a high CC50 and, consequently, a relevant selectivity index. The results findings relevant for the validation of cysteine proteases as a target to combat the parasite, in addition to allowing a greater understanding of the antileishmanial potential of flavonoid analogues.