Discovery of Sustainable Drugs for Neglected Tropical Diseases: Cashew Nut Shell Liquid (CNSL)‐Based Hybrids Target Mitochondrial Function and ATP Production in Trypanosoma brucei. (5th February 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 14:Number 6(2019)
• Page Start: 621
• Page End: 635
• Publication Date: 2019-02-05
• Subjects: antiprotozoal agents -- cashew nut shell liquid -- hybrid drugs -- natural products -- trypanosomiasis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800790
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Don′t eschew the cashew : We synthesized a novel and sustainable series of anti‐trypanosomal hybrids derived from cashew nut shell liquid (CNSL) that target the energy metabolism in Trypanosoma brucei . These compounds alter the ATP levels, mitochondrial membrane potential, and production of reactive oxygen species. Compound 20 showed EC50 values in the low‐micromolar range, no drug resistance, and a good selectivity index.