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.
Martinengo, B., Baldassarri, C., Ilbeigi, K., Alkhalaf, H.E., Sarode, A., Elmahallawy, E.K., et al. (2025). Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts. JOURNAL OF MEDICINAL CHEMISTRY, 68(18), 19438-19462 [10.1021/acs.jmedchem.5c01617].
Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts
Martinengo, Bianca;Bolognesi, Maria Laura
2025
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
