Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development

DNDi Institut Pasteur Korea (IPK) Reconstruction Credit Institution-Federal Ministry of Education and Research (KfW-BMBF)/Germany Medecins Sans Frontieres (Doctors without Borders)/International Korean government (MSIP), Gyeonggi-do KISTI Advocacy for better drugs and access to treatment has boosted the interest in drug discovery and development for Chagas disease, a chronic infection caused by the genetically heterogeneous parasite, Trypanosoma cruzi. in this work new in vitro assays were used to gain a better understanding of the antitrypanosomal properties of the most advanced antichagasic lead and clinical compounds, the nitroheterocyclics benznidazole, nifurtimox and fexinidazole sulfone, the oxaborole AN4169, and four ergosterol biosynthesis inhibitors -posaconazole, ravuconazole, EPL-BS967 and EPL-BS1246. Two types of assays were developed: one for evaluation of potency and efficacy in dose-response against a panel of T. cruzi stocks representing all current discrete typing units (DTUs), and a time-kill assay. Although less potent, the nitroheterocyclics and the oxaborole showed broad efficacy against all T. cruzi tested and were rapidly trypanocidal, whilst ergosterol biosynthesis inhibitors showed variable activity that was both compoundand strain-specific, and were unable to eradicate intracellular infection even after 7 days of continuous compound exposure at most efficacious concentrations. These findings contest previous reports of variable responses to nitroderivatives among different T. cruzi strains and further challenge the introduction of ergosterol biosynthesis inhibitors as new single chemotherapeutic agents for the treatment of Chagas disease. Inst Pasteur Korea, Ctr Neglected Dis Drug Discovery CND3, Songnam, South Korea Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias LNBio, Campinas, SP, Brazil Universidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, Brazil Drugs Neglected Dis Initiat DNDi, Geneva, Switzerland Universidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, Brazil Korean government (MSIP), Gyeonggi-do: 2007-00559 Web of Science