Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

Abstract

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria. According to the World Health Organization, 216 million cases of malaria were reported in 2016 with 445,000 deaths. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Flavonoids are a class of compounds that has been the subject of considerable scientific interest. New developments of flavonoids have made promising advances for the potential treatment of malaria, leishmaniasis, Chagas disease, and dengue, with less toxicity, high efficacy, and improved bioavailability. This review summarizes the current standings of the use of flavonoids to treat malaria and neglected diseases such as leishmaniasis, Chagas disease, and dengue. Natural and synthetic flavonoids are leading compounds that can be used for developing antiprotozoal and antiviral agents. However, detailed studies on toxicity, pharmacokinetics, and mechanisms of action of these compounds are required to confirm the in vitro pharmacological claims of flavonoids for pharmaceutical applications. Highlights In the current review, we have tried to compile recent discoveries on natural and synthetic flavonoids as well as their implication in the treatment of malaria, leishmaniasis, Chagas disease, and dengue. A total of 373 (220 natural and 153 synthetic) flavonoids have been evaluated for antimalarial, antileishmanial, antichagasic, and antidengue activities. Most of these flavonoids showed promising results against the above diseases. Reports on molecular modeling of flavonoid compounds to the disease target indicated encouraging results. Flavonoids can be prospected as potential leads for drug development; however, more rigorously designed studies on toxicity and pharmacokinetics, as well as the quantitative structure–activity relationship studies of these compounds, need to be addressed.

Parasitological and immunological evaluation of a novel chemotherapeutic agent against visceral leishmaniasis

“…Future studies, however, will need to analyse further the mechanism of action of CMt on intra‐macrophage or axenic amastigotes, and use ROS‐chelating substances to evaluate ROS contribution to the effectiveness of CMt. Regardless, other studies investigating plant‐extracted flavonoids as antileishmanial agents have shown also that these molecules function in the parasite mitochondria 17,48 . For instance, a study on the in vitro leishmanicidal activity of strychnobiflavone, a flavonoid isolated from Strychnos pseudoquina St.…”

“…However, no effectively formulated product to treat Leishmania infection has been made available to date. [15][16][17] Flavonoids are secondary metabolites extracted from plants which present diverse biological functions, such as antimicrobial, larvicidal, antiallergic and anti-inflammatory activity. Studies have shown that these molecules can act also as antileishmanial agents.…”

“…Studies have shown that these molecules can act also as antileishmanial agents. [17][18][19] Maclura tinctoria is a plant popularly known as mulberry, taiúva or amarelinho, which belongs to the Moraceae family and is found in tropical countries worldwide. 20,21 Numerous studies have reported that some flavonoids isolated from M tinctoria leaves extracts, 22,23 such as 5,7,3',4'-tetrahydroxy-6,8-diprenylisoflavone (CMt), have neuroprotective activity and anti-Trypanosoma brucei action.…”

“…Several studies evaluating semi‐purified fractions and/or purified molecules have been performed, some of which showing promising results. However, no effectively formulated product to treat Leishmania infection has been made available to date 15‐17 . Flavonoids are secondary metabolites extracted from plants which present diverse biological functions, such as antimicrobial, larvicidal, antiallergic and anti‐inflammatory activity.…”

“…Flavonoids are secondary metabolites extracted from plants which present diverse biological functions, such as antimicrobial, larvicidal, antiallergic and anti‐inflammatory activity. Studies have shown that these molecules can act also as antileishmanial agents 17‐19 . Maclura tinctoria is a plant popularly known as mulberry, taiúva or amarelinho, which belongs to the Moraceae family and is found in tropical countries worldwide 20,21 .…”