Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease

Justin R. Harrison, Sandipan Sarkar, Shahienaz Hampton, Jennifer Riley, Laste Stojanovski, Christer Sahlberg, Pia Appelqvist, Jessey Erath, Vinodhini Mathan, Ana Rodriguez, Marcel Kaiser, Dolores Gonzalez Pacanowska, Kevin D. Read, Nils Gunnar Johansson, Ian H. Gilbert (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.

Original languageEnglish
Pages (from-to)3066-3089
Number of pages24
JournalJournal of Medicinal Chemistry
Volume63
Issue number6
Early online date5 Mar 2020
DOIs
Publication statusPublished - 26 Mar 2020

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