Parasite chemotherapy

Protozoan and helminthic parasitic diseases affect more than 3 billion people worldwide mostly in tropical and subtropical areas. These diseases also have a high prevalence in animals provoking a great health, social and economic loss in the less-developed countries. The development of vaccines is an unachieved goal and drugs currently used for protozoan parasitic diseases such as human African trypanosomiasis (HAT or sleeping sickness) or American trypanosomiasis (Chagas disease) are old, many dating from the colonial era. These drugs have low efficiency, (sometimes severe) side effects, complex administration protocols, and high prices that are unaffordable for the affected countries. Besides, drug resistance is increasingly common. It is therefore urgent to develop new drugs to target these diseases.

Our group is interested in the search for new chemotherapeutic agents against protozoan parasites of the genus Trypanosoma (Trypanosoma brucei and Trypanosoma cruzi), Plasmodium, Leishmania, and Trichomonas.

RESEARCH LINES

Synthesis and optimization of lead compounds derived from nitroindazole and nitroquinoxaline active against T. cruzi, Leishmania and T. vaginalis.

Study of the metabolism and mechanism of action of the nitroderivatives and their targets within the parasite

Discovery of new active molecules against pathogenic protozoa by in silico screening.

Synthesis and optimization of cationic lead compounds against kinetoplastid parasites.

Physico-chemical properties profiling (pKa, logP, solubility).

Study of the mechanism of action and their targets within the parasite (mitochondrion, kDNA, TAO...).

Study of DNA binding by biophysical methods (UV, SPR).

Synthesis of hydroxyquinones as antiparasitic and antitumoral drugs.

Cationic compounds targeting the mitochondrion of protozoan parasites

SELECTED PUBLICATIONS

1) Ebiloma, G.; Balogun, E.; Cueto‐Díaz, E.; De Koning, H.; Dardonville, C. Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi. Med. Res. Rev. 2019, DOI: 10.1002/med.21560.

2) Meco Navas, A; Ebiloma, GU; Martín Domínguez, A; Martínez Benayas, I; Cueto-Diaz, EJ; Saud Alhejely, A; Balogun, EO; Saito, M; Matsui, M; Arai, N; Shiba, T; Harada, S; de Koning, HP; Dardonville, C. SAR of 4-Alkoxybenzoic acid inhibitors of the trypanosome alternative oxidase. ACS Med. Chem. Lett. 2018, 9, 923-928.

3) Ebiloma, G. U.; Díaz Ayuga, T.; 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.; Dardonville, C. 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. Eur. J. Med. Chem. 2018, 150, 385-402.

4) C. Fonseca-Berzal, A. Ibáñez-Escribano, N. Vela, J. Cumella, J. J. Nogal-Ruiz, J. A. Escario, P. B. da Silva, M. M. Batista, M. N. C. Soeiro, S. Sifontes-Rodríguez, A. Meneses-Marcel, A. Gómez-Barrio, V. J. Arán, Antichagasic, leishmanicidal and trichomonacidal activity of 2-benzyl-5-nitroindazole-derived amines, ChemMedChem 2018, 13, 1246-1259.

5) A. Meneses-Marcel, Y. Marrero-Ponce, A. Ibáñez-Escribano, A. Gómez-Barrio, J. A. Escario, S. J. Barigye, E. Terán, C. R. García-Jacas, Y. Machado-Tugores, J. J. Nogal-Ruiz, V. J. Arán-Redó, Drug repositioning for novel antitrichomonas from known antiprotozoan drugs using hierarchical screening, Fut. Med. Chem. 2018, 10, 863-878.

6) R. Martín-Escolano, B. Aguilera-Venegas, C. Marín, Á. Martín-Montes, J. Martín-Escolano, E. Medina-Carmona, V. J. Arán, M. Sánchez-Moreno, Synthesis and biological in vitro and in vivo evaluation of 2-(5-nitro-1-indazolyl)ethylamines and related compounds as potential Chagas disease therapeutic alternative, ChemMedChem 2018, 13, 2104-2118.

7) C. Fonseca-Berzal, V. J. Arán, J. A. Escario, A. Gómez-Barrio, Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi. Parasitol Res. 2018, 117, 3367-3380.

8) Millan, C.; Acosta-Reyes, F.; Lagartera, L.; Ebiloma, G.; Lemgruber, L.; Nué Martinez, J.J.; Saperas, N.; Dardonville, C.; de Koning, H.; Campos, J.L. Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast. Nucleic Acids Res. 2017, 45, 8378-8391.

9) Fueyo González, F. J.; Ebiloma, G. U.; Izquierdo García, C.; Bruggeman, V.; Sánchez Villamañán, J. M.; Donachie, A.; Balogun, E. O.; Inaoka, D. K.; Shiba, T.; Harada, S.; Kita, K.; de Koning, H. P.; Dardonville, C. Conjugates of 2,4-dihydroxybenzoate and salicylhydroxamate and lipocations display potent anti-parasite effects by efficiently targeting the Trypanosoma brucei and Trypanosoma congolense mitochondrion. J. Med. Chem. 2017, 60, 1509–1522.

MEMBERS

Parasite chemotherapy

Vicente J. Arán Redó (Investigador Científico)

Christophe Dardonville (Científico Titular)

María Teresa Molina Orden (Científico Titular)

J. Jonathan Nué Martínez (PhD student)

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