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

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

doi:10.1021/acs.jmedchem.5c01617

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

Bianca Martinengo
, Cecilia Baldassarri
, Kayhan Ilbeigi
, Hamed E. Alkhalaf
, Aditya Sarode
, Ehab Kotb Elmahallawy
, Ba Reum Kwon
, Amos Sarpong Agyei
, Aigerim Abdimanova
, Ludmila Ferreira de Almeida Fiuza
, Raquel Azevedo
, Ketlym da Conceição
, Marcos Meuser Batista
, Ellyêssa Nascimento Borges
, Kleber Santiago Freitas e Silva
, Éder Jéferson Souza Cardoso
, Natália Cipriano Monteiro
, Lais Flavia Nunes Lemes
, Luiz Antonio Soares Romeiro
, Antonio Alonso

Maria de Nazaré Correia Soeiro, Guy Caljon, Bryan W. Brooks, Harry P. De Koning, Maria Laura Bolognesi^*

^*Corresponding author for this work

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Pages (from-to)	19438–19462
Number of pages	25
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	18
Early online date	8 Sept 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c01617
Publication status	Published - 25 Sept 2025

Funding

This research was supported by PON ‘‘Ricerca e Innovazione’’ 2014−2020 program (CUP J35F21003320006) and by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging infectious Diseases (Project no. PE00000007, INF-ACT). The authors gratefully acknowledge support from National Council of Technological and Scientific Development (CNPq #401864/2013-8 (PVE), #312709/2017-0 (DT-2), and #303377/2023-2 (DT-2), from RPT11F (Rede de Plataformas Tecnológicas da Fiocruz, IOC/Fiocruz), from The Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ), National Council for Scientific and Technological Development (CNPq), Oswaldo Cruz Foundation, PAEF/CNPq/Fiocruz, and CAPES, the Fonds Wetenschappelijk Onderzoek Vlaanderen (G033618N), FAPDF Edital 09/2023 #00193-00002046/2023-10, a Daniel Turnberg UK/Middle East Travel Fellowship to E.K.E. and a studentship from Northwest Biosciences to A.S. MNCS is CNPq and FAPERJ researcher. A.A. received a research grant from CNPq (304468/2022-3). The authors sincerely acknowledge Michael G. Bertram, Eli S. J. Thoré and Elisa Uliassi for the helpful discussion and suggestions on ecotoxicological studies. This work was developed within the COST Action OneHealth drugs against parasitic vector-borne diseases in Europe and beyond (OneHealthdrugs) CA21111.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

cations
drug resistance
parasites
salts
toxicity

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Martinengo-etal-JMC-2025-Sustainable-antiparasitic-agents-from-an-agro-industrial-wasteFinal published version, 3.51 MBLicence: CC BY 4.0

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Martinengo, B., Baldassarri, C., Ilbeigi, K., Alkhalaf, H. E., Sarode, A., Elmahallawy, E. K., Kwon, B. R., Agyei, A. S., Abdimanova, A., de Almeida Fiuza, L. F., Azevedo, R., da Conceição, K., Meuser Batista, M., Borges, E. N., Freitas e Silva, K. S., Cardoso, É. J. S., Monteiro, N. C., Nunes Lemes, L. F., Soares Romeiro, L. A., ... Bolognesi, M. L. (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. 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.",

keywords = "cations, drug resistance, parasites, salts, toxicity",

author = "Bianca Martinengo and Cecilia Baldassarri and Kayhan Ilbeigi and Alkhalaf, \{Hamed E.\} and Aditya Sarode and Elmahallawy, \{Ehab Kotb\} and Kwon, \{Ba Reum\} and Agyei, \{Amos Sarpong\} and Aigerim Abdimanova and \{de Almeida Fiuza\}, \{Ludmila Ferreira\} and Raquel Azevedo and \{da Concei{\c c}{\~a}o\}, Ketlym and \{Meuser Batista\}, Marcos and Borges, \{Elly{\^e}ssa Nascimento\} and \{Freitas e Silva\}, \{Kleber Santiago\} and Cardoso, \{{\'E}der J{\'e}ferson Souza\} and Monteiro, \{Nat{\'a}lia Cipriano\} and \{Nunes Lemes\}, \{Lais Flavia\} and \{Soares Romeiro\}, \{Luiz Antonio\} and Antonio Alonso and Soeiro, \{Maria de Nazar{\'e} Correia\} and Guy Caljon and Brooks, \{Bryan W.\} and \{De Koning\}, \{Harry P.\} and Bolognesi, \{Maria Laura\}",

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month = sep,

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doi = "10.1021/acs.jmedchem.5c01617",

language = "English",

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Martinengo, B, Baldassarri, C, Ilbeigi, K, Alkhalaf, HE, Sarode, A, Elmahallawy, EK, Kwon, BR, Agyei, AS, Abdimanova, A, de Almeida Fiuza, LF, Azevedo, R, da Conceição, K, Meuser Batista, M, Borges, EN, Freitas e Silva, KS, Cardoso, ÉJS, Monteiro, NC, Nunes Lemes, LF, Soares Romeiro, LA, Alonso, A, Soeiro, MDNC, Caljon, G, Brooks, BW, De Koning, HP & Bolognesi, ML 2025, 'Sustainable antiparasitic agents from an agro-industrial waste: mitochondria-targeting cashew nutshell liquid-derived phosphonium and ammonium salts', Journal of Medicinal Chemistry, vol. 68, no. 18, pp. 19438–19462. https://doi.org/10.1021/acs.jmedchem.5c01617

TY - JOUR

T1 - Sustainable antiparasitic agents from an agro-industrial waste

T2 - mitochondria-targeting cashew nutshell liquid-derived phosphonium and ammonium salts

AU - Martinengo, Bianca

AU - Baldassarri, Cecilia

AU - Ilbeigi, Kayhan

AU - Alkhalaf, Hamed E.

AU - Sarode, Aditya

AU - Elmahallawy, Ehab Kotb

AU - Kwon, Ba Reum

AU - Agyei, Amos Sarpong

AU - Abdimanova, Aigerim

AU - de Almeida Fiuza, Ludmila Ferreira

AU - Azevedo, Raquel

AU - da Conceição, Ketlym

AU - Meuser Batista, Marcos

AU - Borges, Ellyêssa Nascimento

AU - Freitas e Silva, Kleber Santiago

AU - Cardoso, Éder Jéferson Souza

AU - Monteiro, Natália Cipriano

AU - Nunes Lemes, Lais Flavia

AU - Soares Romeiro, Luiz Antonio

AU - Alonso, Antonio

AU - Soeiro, Maria de Nazaré Correia

AU - Caljon, Guy

AU - Brooks, Bryan W.

AU - De Koning, Harry P.

AU - Bolognesi, Maria Laura

PY - 2025/9/25

Y1 - 2025/9/25

N2 - 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.

AB - 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.

KW - cations

KW - drug resistance

KW - parasites

KW - salts

KW - toxicity

U2 - 10.1021/acs.jmedchem.5c01617

DO - 10.1021/acs.jmedchem.5c01617

M3 - Article

SN - 0022-2623

VL - 68

SP - 19438

EP - 19462

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

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

Abstract

Funding

UN SDGs

Keywords

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