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

Ebiloma, G. U. et al. (2018) 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. European Journal of Medicinal Chemistry, 150, pp. 385-402. (doi:10.1016/j.ejmech.2018.02.075) (PMID:29544150)

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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 parasitemia of mice infected with T. b. rhodesiense (STIB900). These compounds represent a promising new class of potent and selective hits against African trypanosomes.

Item Type:Articles
Additional Information: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 TETFund 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.
Keywords:Organic chemistry, pharmacology, drug discovery, general medicine.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ebiloma, Godwin Unekwuojo and De Koning, Professor Harry and Donachie, Ms Anne Marie
Authors: Ebiloma, G. U., Ayuga, T. D., Balogun, E. O., Gil, L. A., Donachie, A., Kaiser, M., Herraiz, T., Inaoka, D. K., Shiba, T., Harada, S., Kita, K., De Koning, H. P., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:European Journal of Medicinal Chemistry
Publisher:Elsevier
ISSN:0223-5234
ISSN (Online):1768-3254
Published Online:26 February 2018
Copyright Holders:Copyright © 2018 Elsevier Masson SAS.
First Published:First published in European Journal of Medicinal Chemistry 2018
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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