Chagas Disease is a parasitic infection caused by the kinetoplastid protozoan, Trypanosoma cruzi (T. cruzi) and is prevalent throughout Latin America where 7.6 million people are estimated to be infected with the parasite and a further 108 million are considered at risk [1]. Shortcomings of existing therapies, including harmful side-effects and lack of efficacy in the chronic phase of the disease, as well as the increasing occurrence of cases beyond endemic areas, has resulted in numerous international initiatives aimed at developing new drugs for treating Chagas Disease.
In 2009, a luminescence cell-based microorganism primary high throughput screen (HTS) to identify inhibitors of T. cruzi replication was conducted at the BROAD Institute and the results made available on PubChem [2]. As part of an ongoing Chagas drug discovery collaboration funded by the Drugs for Neglected Diseases initiative, we identified compound CID1867212 as an attractive hit from the BROAD screen and confirmed it possessed nanomolar potency against T. cruzi. Focussed medicinal chemistry efforts have successfully modified the starting structure to produce a range of analogues with improved potency and pharmacokinetic profiles.
This poster will summarise the CID1867212 medicinal chemistry program and include the synthesis, in vitro and in vivo efficacy and pharmacokinetic data for key analogues.