Imidazole derivatives as promising agents for the treatment of Chagas disease †.

Imidazole derivatives as promising agents for the treatment of Chagas disease†. Antimicrob Agents Chemother. 2019 Jan 22;: Authors: de Araújo JS, Garcia-Rubia A, Sebastian-Perez V, Kalejaiye TD, Bernardino da Silva P, Fonseca-Berzal CR, Maes L, De Koning HP, Soeiro MNC, Gil C 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 reve...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research