Innovative, sustainable therapies are urgently needed for neglected vector-borne parasitic diseases. In this study, we leveraged cashew nutshell liquid (CNSL), an agro-industrial byproduct, to develop biobased phosphonium and ammonium salts (5–25) targeting parasite mitochondria. By combining CNSL-derived C8 alkyl chains with lipophilic cations, we synthesized novel compounds exhibiting highly potent in vitro and ex vivo activity against Trypanosoma and Leishmania spp., including veterinary-relevant strains like T. b. evansi and T. b. equiperdum. Compounds 5 and 7 outperformed reference drugs, demonstrating subnanomolar efficacy against Trypanosoma brucei spp., high selectivity indices (>1000), and no cross-resistance with current therapies, underscoring their potential as next-generation antitrypanosomal agents. Reduced activity against T. brucei overexpressing alternative oxidase and against Trypanosoma congolense supports a mitochondrial mechanism. Preliminary bioassays in zebrafish and Daphnia magna indicated ecotoxicity lower than antiparasitic activity. These CNSL-derived agents represent promising, environmentally safer antiparasitic candidates aligned with One Health and Green Chemistry principles.

The phytochemical screening of extracts of Tacca leontopetaloides tubers has afforded the isolation of two novel chalcones, tarkalynins A and B, along with taccalonolide A and its 12-propanoate. The screening of Zanthoxylum zanthoxyloides stem bark yielded taraxerol acetate, dihydrochelerythrin and fagaramide. These compounds were obtained through column and thin-layer chromatography and identified using NMR and LC-HRMS. The compounds were tested against Trypanosoma brucei brucei s427 and its multi-drug-resistant clone B48, against Trypanosoma evansi, Trypanosoma equiperdum and Trypanosoma congolense, and against Leishmania mexicana. Cytotoxicity was tested against the human HEK293 cell line. The highest activities were observed with dihydrochelerythrin and fagaramide against T. b. brucei s427 and B48, T. evansi, and L. mexicana, with EC₅₀ values of 1.37, 2.559, 1.09, and 5.44 µM and 17.8, 10.9, 10.9, and 13.3 µM, respectively. In addition, tarkalynin A and taraxerol acetate displayed promising activity against T. equiperdum (EC₅₀ = 21.4 and 21.3 µM, respectively). None of these compounds showed significant cross-resistance with existing trypanocides (RF ≈ 1; p > 0.05). The compounds displayed low toxicity to human cells, with most exhibiting no growth inhibition at concentrations of 100, or even 300 µM. This report provides further evidence of the potential use of natural products for combating parasitic diseases.

Phytochemical screening of extracts of Tacca leontopetaloides tubers, has afforded the isolation of two novel chalcones, tarkalynins A and B, along with taccalonolide A and its 12-propanoate. Screening of Zanthoxylum zanthoxyloides stem bark yielded taraxerol acetate, dihydrochelerythrin and fagaramide. These compounds were obtained through column and thin-layer chromatography and identified using NMR and LC-HRMS. The compounds were tested against Trypanosoma brucei brucei s427 and its multi-drug-resistant clone B48, against T. evansi, T. equiperdum, T. congolense, and against L. mexicana. Cytotoxicity was tested against the human HEK293 cell line. The highest activities were observed with dihydrochelerythrin and fagaramide against T. b. brucei s427 and B48, T. evansi, and L. mexicana with EC50 values of 0.5, 0.9, 0.4, and 1.9 µg/mL and of 4.4, 2.7, 2.7, and 3.3 µg/mL, respectively. In addition, tarkalynin A and taraxerol acetate displayed promising activity against T. equiperdum (EC50 = 7.1 and 9.98 µg/mL, respectively). None of these compounds showed significant cross-resistance with existing trypanocides (RF ≈ 1; P>0.05). The compounds displayed low toxicity to human cells, with most exhibiting no growth inhibition at concentrations of 100 or 200 µg/mL. This report provides further evidence of the potential of natural products for combating parasitic diseases.