Sustainable antiparasitic agents from an agro-industrial waste : mitochondria-targeting cashew nutshell liquid-derived phosphonium and ammonium salts

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Martinengo, Bianca and Baldassarri, Cecilia and Ilbeigi, Kayhan and Alkhalaf, Hamed E. and Sarode, Aditya and Elmahallawy, Ehab Kotb and Kwon, Ba Reum and Agyei, Amos Sarpong and Abdimanova, Aigerim and de Almeida Fiuza, Ludmila Ferreira and Azevedo, Raquel and da Conceição, Ketlym and Meuser Batista, Marcos and Borges, Ellyêssa Nascimento and Freitas e Silva, Kleber Santiago and Cardoso, Éder Jéferson Souza and Monteiro, Natália Cipriano and Nunes Lemes, Lais Flavia and Soares Romeiro, Luiz Antonio and Alonso, Antonio and Soeiro, Maria de Nazaré Correia and Caljon, Guy and Brooks, Bryan W. and De Koning, Harry P. and Bolognesi, Maria Laura (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. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.5c01617)

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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.

ORCID iDs

Martinengo, Bianca, Baldassarri, Cecilia, Ilbeigi, Kayhan, Alkhalaf, Hamed E., Sarode, Aditya ORCID logoORCID: https://orcid.org/0000-0001-7521-1257, Elmahallawy, Ehab Kotb, Kwon, Ba Reum, Agyei, Amos Sarpong, Abdimanova, Aigerim, de Almeida Fiuza, Ludmila Ferreira, Azevedo, Raquel, da Conceição, Ketlym, Meuser Batista, Marcos, Borges, Ellyêssa Nascimento, Freitas e Silva, Kleber Santiago, Cardoso, Éder Jéferson Souza, Monteiro, Natália Cipriano, Nunes Lemes, Lais Flavia, Soares Romeiro, Luiz Antonio, Alonso, Antonio, Soeiro, Maria de Nazaré Correia, Caljon, Guy, Brooks, Bryan W., De Koning, Harry P. and Bolognesi, Maria Laura;
CORE (COnnecting REpositories)