Abstract
Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 μM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 μM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.
Highlights
Caused by the protozoan Trypanosoma cruzi and endemic in 21 countries in Latin America, Chagas disease kills ∼10,000 people each year1
We report the discovery of a series of reversible cruzain inhibitors showing promising trypanocidal activity and low toxicity
The imide derivative 3a (Figure 1A), a reversible cruzain inhibitor that was previously identified from a virtual high-throughput screening (HTS) combined approach (Ferreira et al, 2010), was taken as the initial hit for molecular optimization
Summary
Caused by the protozoan Trypanosoma cruzi and endemic in 21 countries in Latin America, Chagas disease kills ∼10,000 people each year. Caused by the protozoan Trypanosoma cruzi and endemic in 21 countries in Latin America, Chagas disease kills ∼10,000 people each year1 This neglected tropical disease has reached nonendemic regions, affecting 8 million people worldwide and putting another 25 million at risk of infection. Structure-Based Design of Cruzain Inhibitors reduction in productivity of the affected populations significantly impact the economies of the endemic regions These economic and social burdens can be translated in numbers that estimate losses of more than US $7.2 billion per year and ∼243,600 disability-adjusted life years (DALYs) due to Chagas disease (GBD DALYs and HALE Collaborators, 2016; Arnal et al, 2019)
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