1. 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
- Author
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Marcel Kaiser, Kiyoshi Kita, Godwin U. Ebiloma, Emmanuel Oluwadare Balogun, Tomoo Shiba, Christophe Dardonville, Anne M. Donachie, Lucía Abad Gil, Shigeharu Harada, Harry P. de Koning, Daniel Ken Inaoka, Tomás Herraiz, Teresa Díaz Ayuga, Comunidad de Madrid, University of Glasgow, Red de Investigación Cooperativa en Enfermedades Tropicales (España), Ministerio de Economía, Industria y Competitividad (España), United Nations Children's Fund, and World Bank Group
- Subjects
0301 basic medicine ,Trypanosoma ,Alternative oxidase ,Trypanosoma congolense ,Trypanosoma brucei brucei ,Trypanocide ,Parabens ,Trypanosoma brucei ,Mitochondrial Proteins ,Structure-Activity Relationship ,03 medical and health sciences ,Diminazene ,Parasitic Sensitivity Tests ,Trypanosomiasis ,Cations ,Trypanosome alternative oxidase (TAO) ,Drug Discovery ,medicine ,T. congolense ,T. b. rhodesiense ,Plant Proteins ,Parasite respiration ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,Wild type ,Mitochondrial targeting ,Quinolinium salt ,General Medicine ,biology.organism_classification ,Trypanocidal Agents ,Amino acid ,030104 developmental biology ,Enzyme ,SHAM ,Biochemistry ,chemistry ,Hydroxybenzoate ,Lipophilic cation ,Benzaldehydes ,Oxidoreductases ,medicine.drug ,Pentamidine ,Triphenylphosphonium salt (TPP) - 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 (IC) 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., This work was funded by the Spanish Ministerio de Economia y Competitividad (SAF2015-66690-R). This investigation also received financial support (ID No. B40103 to EOB) from TDR, the Special Programme for Research and Training in Tropical Diseases (co-sponsored by UNICEF, UNDP, the World Bank and WHO). G. U. Ebiloma was supported by a TET-Fund studentship from the government of Nigeria and by a Mac Robertson Travel Scholarship from the College of Medical, Veterinary and Life Sciences of the University of Glasgow.
- Published
- 2018