title: Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development.
abstract: 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 compound- and 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.
authors.affiliation: 1] Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, South Korea [2] Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, Brazil.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Moraes
authors.affiliation: Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, South Korea.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Giardini
authors.affiliation: Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, South Korea.
authors.forename: Hwayoung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, Brazil.
authors.forename: Caio H
authors.initials: CH
authors.lastname: Franco
authors.affiliation: Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, Brazil.
authors.forename: Adalberto M
authors.initials: AM
authors.lastname: Araujo-Junior
authors.affiliation: Depto. de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Schenkman
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
authors.affiliation: 1] Center for Neglected Diseases Drug Discovery (CND3), Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, South Korea [2] Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, Brazil.
authors.forename: Lucio H
authors.initials: LH
authors.lastname: Freitas-Junior
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058886:Sterol 14-Demethylase / Q000737:chemistry* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism
chemical_list: D058888:14-alpha Demethylase Inhibitors; D006571:Heterocyclic Compounds; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D058886:Sterol 14-Demethylase
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