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
  • 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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