Structure-Activity Relationships for a Series of Benzimidazole Derivatives as Cruzain Inhibitors

Chagas disease affects 8 million people worldwide, mostly in Latin America, causing more than 10,000 deaths per year and putting at risk of infection more than 25 million people. Pharmacotherapy of Chagas disease is restricted to a few options whose inefficacy and associated adverse effects demonstrate the urgent demand for novel, safe and effective drugs1. In this study, 3D quantitative structure-activity relationship (QSAR) models were developed for a series of inhibitors of the major cysteine protease from Trypanosoma cruzi (cruzain, EC 3.4.22.51)2 using the Comparative Molecular Similarity Index Analysis method (CoMSIA). The data set consists of 27 molecules synthesized and evaluated in our laboratory, having a benzimidazole core as the mutual substructure. Training and test sets were selected by applying a principal component analysis on the entire series. The molecular alignment was obtained by a structure-based approach, whereby the inhibitors were docked into the binding site of cruzain. The final CoMSIA model, weighted by the standard deviation*coefficient (Stdev*Coeff) region focusing technique, displayed suitable statistical consistency (r2 = 0.98 and q2 = 0.75) and predictive ability for test set compounds (r2pred = 0.82). The 3D contour plots revealed relevant properties of the inhibitors closely related with their corresponding biological activity (Figure 1). These findings support the use of the CoMSIA model to guide the conception of novel cruzain inhibitors within the chemical space delimited by the studied benzimidazole series.