Imidazole derivatives as promising agents for the treatment of Chagas disease

Siciliano de Araújo, J., Garcia-Rubia, A., Sebastian-Perez, V., Kalejaiye, T. D., Bernardino da Silva, P., Fonseca-Berzal, C. R., Maes, L., De Koning, H. P. , de Nazaré Correia Soeiroa, M. and Gil, C. (2019) Imidazole derivatives as promising agents for the treatment of Chagas disease. Antimicrobial Agents and Chemotherapy, 63(4), e02156-18. (doi:10.1128/AAC.02156-18)

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Abstract

More than 100 years later after being firstly described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continent but has become a global health threat. Current therapies, nifurtimox and benznidazole (Bz), are far from being adequate due to undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypical evaluation in T.cruzi of a new class of imidazole compounds, discovered in a previous phenotypic screening against different trypanosomatids and designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to Bz prompted a synthesis program of hit optimization and extended SAR, aimed at improving drug-like properties such as aqueous solubility, resulting in additional hits with IC50 similar to Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC50 concentration, that were consistent with induced autophagy and osmotic stress - mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP, confirming that inhibition of T.cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T.cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:kalejaiye, Titilola and De Koning, Professor Harry
Authors: Siciliano de Araújo, J., Garcia-Rubia, A., Sebastian-Perez, V., Kalejaiye, T. D., Bernardino da Silva, P., Fonseca-Berzal, C. R., Maes, L., De Koning, H. P., de Nazaré Correia Soeiroa, M., and Gil, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Published Online:22 January 2019
Copyright Holders:Copyright © 2019 American Society for Microbiology
First Published:First published in Antimicrobial Agents and Chemotherapy 63(4):e02156-18
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY