2. Academic Validation
  3. Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts

Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts

  • J Med Chem. 2025 Sep 25;68(18):19438-19462. doi: 10.1021/acs.jmedchem.5c01617.
Bianca Martinengo 1,  Cecilia Baldassarri 2 3,  Kayhan Ilbeigi 4,  Hamed E Alkhalaf 3,  Aditya Sarode 3 5,  Ehab Kotb Elmahallawy 3 6 7,  Ba Reum Kwon 8,  Amos Sarpong Agyei 8,  Aigerim Abdimanova 8,  Ludmila Ferreira de Almeida Fiuza 9,  Raquel Azevedo 9,  Ketlym da Conceição 9,  Marcos Meuser Batista 9,  Ellyêssa Nascimento Borges 10,  Kleber Santiago Freitas E Silva 10,  Éder Jéferson Souza Cardoso 11,  Natália Cipriano Monteiro 12,  Lais Flavia Nunes Lemes 12,  Luiz Antonio Soares Romeiro 12,  Antonio Alonso 11,  Maria de Nazaré Correia Soeiro 9,  Guy Caljon 4,  Bryan W Brooks 8 13,  Harry P De Koning 3,  Maria Laura Bolognesi 1
Affiliations

Affiliations

  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum─University of Bologna, Via Belmeloro 6, Bologna 40126, Italy.
  • 2 Medicinal Chemistry Unit, School of Pharmacy, Chemistry Interdisciplinary Project (ChIP), University of Camerino, Via Madonna delle Carceri, Camerino 62032, Italy.
  • 3 School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G43 2DX, U.K.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, 2610 Wilrijk, Belgium.
  • 5 Department of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • 6 Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt.
  • 7 Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), Unidad de Investigación Zoonosis y Enfermedades Emergentes (ENZOEM), Departamento de Sanidad Animal, Universidad de Córdoba, Córdoba 14071, Spain.
  • 8 Department of Environmental Science, Baylor University, Waco, Texas 76798-7266, United States.
  • 9 Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fiocruz. Avenida Brasil 4365, Manguinhos, Rio de Janeiro CEP 21040360, Brazil.
  • 10 Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Goiás 74605-220, Brazil.
  • 11 Instituto de Física, Universidade Federal de Goiás, Goiânia, Goiás 74690-900, Brazil.
  • 12 Laboratório de Desenvolvimento de Inovaçõ Terapêutica, Centro de Medicina Tropical, Faculdade de Medicina, Universidade de Brasília, Brasília 70910-900, Brazil.
  • 13 Department of Public Health, Baylor University, Waco, Texas 76798-7343, United States.
PMID: 40920168 DOI: 10.1021/acs.jmedchem.5c01617
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.

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