Discovery of sustainable drugs for neglected tropical diseases: Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei

Michela Cerone, Elisa Uliassi, Federica Prati, Godwin U. Ebiloma, Leandro Lemgruber, Christian Bergamini, David G. Watson, Thais de A. M. Ferreira, Gabriella Simões Heyn Roth Cardoso, Luiz A. Soares Romeiro, Harry P. de Koning, Maria Laura Bolognesi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.

LanguageEnglish
Pages621-635
Number of pages15
JournalChemMedChem
Volume14
Issue number6
Early online date5 Feb 2019
DOIs
Publication statusPublished - 22 Mar 2019

Fingerprint

Anacardium
Neglected Diseases
Trypanosoma brucei brucei
Nuts
Drug Discovery
African Trypanosomiasis
Adenosine Triphosphate
Mitochondria
Depolarization
Prodrugs
Liquids
Cytotoxicity
Merging
Pharmaceutical Preparations
Waste Products
Industrial plants
Reactive Oxygen Species
Trypanosomiasis
Cells
Mitochondrial Membranes

Keywords

  • antiprotozoal agents
  • cashew nut shell liquid
  • hybrid drugs
  • natural products
  • trypanosomiasis

Cite this

Cerone, Michela ; Uliassi, Elisa ; Prati, Federica ; Ebiloma, Godwin U. ; Lemgruber, Leandro ; Bergamini, Christian ; Watson, David G. ; de A. M. Ferreira, Thais ; Roth Cardoso, Gabriella Simões Heyn ; Soares Romeiro, Luiz A. ; de Koning, Harry P. ; Bolognesi, Maria Laura. / Discovery of sustainable drugs for neglected tropical diseases : Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei. In: ChemMedChem. 2019 ; Vol. 14, No. 6. pp. 621-635.
@article{325af40f59fe41c7b092ff2ab71a0a9b,
title = "Discovery of sustainable drugs for neglected tropical diseases: Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei",
abstract = "In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.",
keywords = "antiprotozoal agents, cashew nut shell liquid, hybrid drugs, natural products, trypanosomiasis",
author = "Michela Cerone and Elisa Uliassi and Federica Prati and Ebiloma, {Godwin U.} and Leandro Lemgruber and Christian Bergamini and Watson, {David G.} and {de A. M. Ferreira}, Thais and {Roth Cardoso}, {Gabriella Sim{\~o}es Heyn} and {Soares Romeiro}, {Luiz A.} and {de Koning}, {Harry P.} and Bolognesi, {Maria Laura}",
year = "2019",
month = "3",
day = "22",
doi = "10.1002/cmdc.201800790",
language = "English",
volume = "14",
pages = "621--635",
journal = "ChemMedChem",
issn = "1860-7179",
number = "6",

}

Cerone, M, Uliassi, E, Prati, F, Ebiloma, GU, Lemgruber, L, Bergamini, C, Watson, DG, de A. M. Ferreira, T, Roth Cardoso, GSH, Soares Romeiro, LA, de Koning, HP & Bolognesi, ML 2019, 'Discovery of sustainable drugs for neglected tropical diseases: Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei' ChemMedChem, vol. 14, no. 6, pp. 621-635. https://doi.org/10.1002/cmdc.201800790

Discovery of sustainable drugs for neglected tropical diseases : Cashew Nut Shell Liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei. / Cerone, Michela; Uliassi, Elisa; Prati, Federica; Ebiloma, Godwin U.; Lemgruber, Leandro; Bergamini, Christian; Watson, David G.; de A. M. Ferreira, Thais; Roth Cardoso, Gabriella Simões Heyn; Soares Romeiro, Luiz A.; de Koning, Harry P.; Bolognesi, Maria Laura.

In: ChemMedChem, Vol. 14, No. 6, 22.03.2019, p. 621-635.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of sustainable drugs for neglected tropical diseases

T2 - ChemMedChem

AU - Cerone, Michela

AU - Uliassi, Elisa

AU - Prati, Federica

AU - Ebiloma, Godwin U.

AU - Lemgruber, Leandro

AU - Bergamini, Christian

AU - Watson, David G.

AU - de A. M. Ferreira, Thais

AU - Roth Cardoso, Gabriella Simões Heyn

AU - Soares Romeiro, Luiz A.

AU - de Koning, Harry P.

AU - Bolognesi, Maria Laura

PY - 2019/3/22

Y1 - 2019/3/22

N2 - In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.

AB - In the search for effective and sustainable drugs for human African trypanosomiasis (HAT), we developed hybrid compounds by merging the structural features of quinone 4 (2-phenoxynaphthalene-1,4-dione) with those of phenolic constituents from cashew nut shell liquid (CNSL). CNSL is a waste product from cashew nut processing factories, with great potential as a source of drug precursors. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multidrug-resistant strains, T. congolense, and a human cell line. The most potent activity was found against T. b. brucei, the causative agent of HAT. Shorter-chain derivatives 20 (2-(3-(8-hydroxyoctyl)phenoxy)-5-methoxynaphthalene-1,4-dione) and 22 (5-hydroxy-2-(3-(8-hydroxyoctyl)phenoxy)naphthalene-1,4-dione) were more active than 4, displaying rapid micromolar trypanocidal activity, and no human cytotoxicity. Preliminary studies probing their mode of action on trypanosomes showed ATP depletion, followed by mitochondrial membrane depolarization and mitochondrion ultrastructural damage. This was accompanied by reactive oxygen species production. We envisage that such compounds, obtained from a renewable and inexpensive material, might be promising bio-based sustainable hits for anti-trypanosomatid drug discovery.

KW - antiprotozoal agents

KW - cashew nut shell liquid

KW - hybrid drugs

KW - natural products

KW - trypanosomiasis

UR - http://www.scopus.com/inward/record.url?scp=85061205957&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201800790

DO - 10.1002/cmdc.201800790

M3 - Article

VL - 14

SP - 621

EP - 635

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 6

ER -