Discovery of sustainable drugs for neglected tropical diseases: cashew nut shell liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei

In a search for effective and sustainable treatments for trypanosomiasis, we developed a library of hybrid compounds by merging the structural features of a previously synthesized quinone hit (4) with those of long‐chain phenolic constituents from cashew nut shell liquid (CNSL). CNSL is an agro‐waste product from cashew nut processing factories with great potential as a precursor for the production of drugs. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multi‐drug resistant strains (B48, ISMR1, and aqp2/aqp3‐KO), T. congolense, and a human cell line (HFF). The most potent activity was found against T. b. brucei, the causative agent of African trypanosomiasis. Shorter‐chain derivatives were more active than the starting hit in parasite growth inhibition, displaying rapid trypanocidal activity with low micromolar EC50 values, but no discernable toxicity on human cell lines. Preliminary studies probing their mode of action on trypanosomes showed depletion of cellular ATP, followed by the depolarization of the mitochondrial membrane and ultrastructural damage to the mitochondrion. This was accompanied by the production of high levels of reactive oxygen species. We envisage that such hybrid compounds, obtained from renewable and inexpensive material, might be promising bio‐based, sustainable hits for anti‐trypanosomatid drug discovery.