Events7th International Electronic Conference on Medicinal Chemistry
Event submissions
Published
with-doi10.3390/ECMC2021-11520
This submission belongs to the session S7. Round table on infectious diseases of the event 7th International Electronic Conference on Medicinal Chemistry
Published date
03 Nov, 2021
Academic Editor
author-avatarJean Jacques Vanden Eynde
Citation
David Cisneros, Eduardo Cueto, Godwin Ebiloma, Christophe Dardonville, Harry De Koning, Tomoo Shiba, Marzuq Ungogo, Shun Matsushiro, Tania Medina, Teresa Bernal, Rebecca Chevillard, Ms. Ootani, Ms. Kojima, Synthesis and SAR studies of a new trypanosome alternative oxidase inhibitors: imidazoline and benzamidine derivatives, in Proceedings of 7th International Electronic Conference on Medicinal Chemistry, 1 November–30 November 2021, MDPI: Basel, Switzerland, doi: 10.3390/ECMC2021-11520
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Synthesis and SAR studies of a new trypanosome alternative oxidase inhibitors: imidazoline and benzamidine derivatives

David Cisneros 1
Eduardo Cueto 1
Tania Medina 1
Rebecca Chevillard 1
Teresa Bernal 1
Godwin Ebiloma 2
Marzuq Ungogo 3
Ms. Ootani 4
Shun Matsushiro 4
Ms. Kojima 4
Tomoo Shiba 4
Harry De Koning 3
image
Christophe Dardonville 1
1. Instituto de Química Médica, IQM–CSIC, Juan de la Cierva 3, E–28006 Madrid, Spain.
2. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK. Graduate School of S
3. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
4. Graduate School of Science and Technology, Department of Applied Biology, Kyoto Institute of Technology, Kyoto
Abstract

Sleeping sickness or human African trypanosomiasis (HAT), is a vector-borne parasitic disease. It is caused by infection with protozoan parasites belonging to the genus Trypanosoma (T. brucei sp.). Without treatment, the disease is usually fatal.

Our research of a novel and effective chemotherapy of HAT is based on the inhibition of the Trypanosome Alternative Oxidase (TAO). TAO is essential for the respiration of bloodstream form trypomastigotes because it is the only enzyme available to re-oxidize the NADH produced during glycolysis. This enzyme, which is conserved among trypanosome subspecies and has no counterpart in mammalian cells, is a validated drug target against trypanosomes.

In previous studies, the structure – activity relationships (SAR) of different TAO inhibitors derived from 4-hydroxybenzoate and 4-alkoxybenzaldehyde was investigated. These compounds were shown to exhibit TAO inhibitory activity at the nanomolar level, showing trypanocidal activity in in vitro and in vivo assays.

In the current study, new analogs have been synthesized with the aim of extending the SAR studies of TAO inhibitors. In this case, the ester bond has been replaced by an amide bond, which is more metabolically stable. In addition, new cationic groups such as benzamidinium, 2-phenylimidazolin-3-ium and 2- (phenylamino) imidazolin-3-ium cations have been incorporated.

We gratefully acknowledge Ministerio de Ciencia, Innovación y Universidades (project RTI2018-093940-B-I00), for financial support.

Keywords
Trypanosome alternative oxidase (TAO) inhibitor
Trypanosoma brucei
benzamidine
imidazoline
structure – activity relationships (SAR).
Poster
ECMC 2021_Cisneros Cañas, DAVID-CD.pdf
ECMC 2021_Cisneros Cañas, DAVID-CD.pdf
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