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

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 e...

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Published in:European journal of medicinal chemistry 2018-04, Vol.150, p.385-402
Main Authors: Ebiloma, Godwin U., Ayuga, Teresa Díaz, Balogun, Emmanuel O., Gil, Lucía Abad, Donachie, Anne, Kaiser, Marcel, Herraiz, Tomás, Inaoka, Daniel K., Shiba, Tomoo, Harada, Shigeharu, Kita, Kiyoshi, de Koning, Harry P., Dardonville, Christophe
Format: Article
Language:English
Subjects:
Benzaldehydes - chemical synthesis
Benzaldehydes - chemistry
Benzaldehydes - pharmacology
Cations - chemistry
Cations - pharmacology
Dose-Response Relationship, Drug
Lipophilic cation
Mitochondrial Proteins - antagonists & inhibitors
Mitochondrial Proteins - metabolism
Mitochondrial targeting
Molecular Structure
Oxidoreductases - antagonists & inhibitors
Oxidoreductases - metabolism
Parabens - chemical synthesis
Parabens - chemistry
Parabens - pharmacology
Parasite respiration
Parasitic Sensitivity Tests
Plant Proteins - antagonists & inhibitors
Plant Proteins - metabolism
Quinolinium salt
SHAM
Structure-Activity Relationship
T. b. rhodesiense
T. congolense
Triphenylphosphonium salt (TPP)
Trypanocidal Agents - chemical synthesis
Trypanocidal Agents - chemistry
Trypanocidal Agents - pharmacology
Trypanocide
Trypanosoma - drug effects
Trypanosoma - enzymology
Trypanosoma brucei
Trypanosoma brucei brucei - drug effects
Trypanosoma congolense - drug effects
Trypanosome alternative oxidase (TAO)
Trypanosomiasis
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Summary: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. [Display omitted] •The physiologically relevant ΔMTS-TAO was expressed and purified for the first time.•Nanomolar range inhibitors of ΔMTS-TAO were discovered.•The inhibitors displayed nanomolar range EC50 values against WT and drug-resistant strains of T. brucei and T. congolense.•Compounds' metabolic stability in liver microsomes and mouse serum was studied.•Compounds 15 and 16 showed in vivo activity against T. b. rhodesiense.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.02.075