Abstract
In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2‐phenoxynaphthalene‐1,4‐dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug‐resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter‐chain derivatives 20 (2‐(3‐(8‐hydroxyoctyl)phenoxy)‐5‐methoxynaphthalene‐1,4‐dione) and 22 (5‐hydroxy‐2‐(3‐(8‐hydroxyoctyl)phenoxy)naphthalene‐1,4‐dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio‐based sustainable hits for anti‐trypanosomatid drug discovery.
Highlights
Neglected tropical diseases (NTD) are a group of 17 highly debilitating and potentially fatal poverty-related diseases
We explore the use of a waste product of food production, the cashew nut shell liquid (CNSL), as a cheap and abundant source of new anti-infective agents for use against NTD
We present clear evidence for mitochondrial targeting in trypanosomes, especially the Transmission electron microscopy (TEM) pictures are convincing, with mitochondrial damage but no other ultrastructural changes observed after just 4 h incubation with 1 EC50 of 22
Summary
The control and elimination of HAT, which are declared goals of the WHO,[1] would be a major step in the reduction of the overall burden of tropical disease that continues to limit development in sub-Saharan Africa.[4] HAT transmission is limited to the tsetse belt, comprising much of sub-Saharan Africa, the risk of HAT in travelers and migrants, albeit low, cannot be overlooked.[5] animal African trypanosomiasis (AAT) has an enormous impact on African agriculture and food security This condition is caused by related trypanosome species including T. b. Thanks to the presence of a naphthoquinone moiety, 4 was shown to generate reactive oxygen species
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