Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense.

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Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense.

Publicated to:EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 150 385-402 - 2018-04-25 150(), DOI: 10.1016/j.ejmech.2018.02.075

Authors: Ebiloma, Godwin U; Diaz Ayuga, Teresa; Balogun, Emmanuel O; Abad Gil, Lucia; Donachie, Anne; Kaiser, Marcel; Herraiz, Tomas; Inaoka, Daniel K; Shiba, Tomoo; Harada, Shigeharu; Kita, Kiyoshi; de Koning, Harry P; Dardonville, Christophe

Affiliations

;Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan - Author

;Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Japan - Author

;Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom - Author

;Instituto de Ciencia y Tecnología de Alimentos y Nutrición, ICTAN-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain - Author

;Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain - Author

;Swiss Tropical and Public Health Institute, Socinstrasse, 57, CH-4002 Basel, Switzerland - Author

Ahmadu Bello Univ, Dept Biochem, Zaria 2222, Nigeria - Author

CSIC - Author

CSIC, ICTAN, Juan Cierva 3, E-28006 Madrid, Spain - Author

CSIC, IQM, Juan Cierva 3, E-28006 Madrid, Spain - Author

Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria - Author

Department of Biochemistry, Kogi State University, Anyigba, Nigeria - Author

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom - Author

Kogi State Univ, Dept Biochem, Anyigba, Nigeria - Author

Kyoto Inst Technol, Dept Appl Biol, Kyoto 6068585, Japan - Author

Nagasaki Univ, Sch Trop Med & Global Hlth, Nagasaki 8528523, Japan - Author

School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, 852-8523, Japan - Author

Swiss Trop & Publ Hlth Inst, Socinstr 57, CH-4002 Basel, Switzerland - Author

Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland - Author

Univ Tokyo, Grad Sch Med, Dept Biomed Chem, Tokyo, Japan - Author

Abstract

African trypanosomiasis is a neglected parasitic disease that is still of great public health relevance, and a severe impediment to agriculture in endemic areas. The pathogens possess certain unique metabolic features that can be exploited for the development of new drugs. Notably, they rely on an essential, mitochondrially-localized enzyme, Trypanosome Alternative Oxidase (TAO) for their energy metabolism, which is absent in the mammalian hosts and therefore an attractive target for the design of safe drugs. In this study, we cloned, expressed and purified the physiologically relevant form of TAO, which lacks the N-terminal 25 amino acid mitochondrial targeting sequence (ΔMTS-TAO). A new class of 32 cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde inhibitors was designed and synthesized, enabling the first structure-activity relationship studies on ΔMTS-TAO. Remarkably, we obtained compounds with enzyme inhibition values (IC50) as low as 2 nM, which were efficacious against wild type and multidrug-resistant strains of T. brucei and T. congolense. The inhibitors 13, 15, 16, 19, and 30, designed with a mitochondrion-targeting lipophilic cation tail, displayed trypanocidal potencies comparable to the reference drugs pentamidine and diminazene, and showed no cross-resistance with the critical diamidine and melaminophenyl arsenical classes of trypanocides. The cationic inhibitors 15, 16, 19, 20, and 30 were also much more selective (900 - 344,000) over human cells than the non-targeted neutral derivatives (selectivity >8-fold). A preliminary in vivo study showed that modest doses of 15 and 16 reduced parasitaemia of mice infected with T. b. rhodesiense (STIB900). These compounds represent a promising new class of potent and selective hits against African trypanosomes.Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Keywords

4-hydroxybenzoic acidAlternative oxidaseBenzaldehydesCationsDose-response relationship, drugLipophilic cationMitochondrial proteinsMitochondrial targetingMolecular structureOxidoreductasesParabensParasite respirationParasitic sensitivity testsPlant proteinsQuinolinium saltShamStructure-activity relationshipT. b. rhodesienseT. congolenseT. b. rhodesienseT. congolenseTriphenylphosphonium salt (tpp)Trypanocidal agentsTrypanocideTrypanosomaTrypanosoma bruceiTrypanosoma brucei bruceiTrypanosoma congolenseTrypanosome alternative oxidase (tao)Trypanosomiasis

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The work has been published in the journal EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position 5/61, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Medicinal. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.25. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

Weighted Average of Normalized Impact by the Scopus agency: 1.15 (source consulted: FECYT Feb 2024)
Field Citation Ratio (FCR) from Dimensions: 2.33 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-16, the following number of citations:

WoS: 23
Scopus: 26
Europe PMC: 4
OpenCitations: 25

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This work has been carried out with international collaboration, specifically with researchers from: Japan; Niger; Switzerland; United Kingdom.

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