Identification, Structure–Activity Relationship (SAR), and Biological Evaluation of New Chemical Series as Malaria Parasite PfGCN5 Bromodomain Inhibitors

Abstract

Despite considerable progress in prevention, treatment, and eradication efforts, malaria continues to impose a significant public health and socioeconomic burden for many countries around the globe. With the effectiveness of current treatment options partially or totally compromised due to resistance, the validation of new targets and the development of new drugs that can reach the demanding standards required for the treatment of this disease represent an urgent and considerable challenge. Herein, we report the evaluation of approximately 48 200-compound library selected from the GSK collection against PfGCN5. From the 6 initial hits with pIC50 > 5, two compounds were progressed for further in vitro profiling and optimization. Computational and medicinal chemistry efforts delivered significantly improved compounds 21h and 41d with pIC50 within the submicromolar range (pIC50 6.6 and 7.0, respectively), but unfortunately, the lead compounds did not show potent in vitro antiparasitic activity. Although further studies are still necessary, our initial data suggest that targeting PfGCN5 to develop new antimalarial compounds might be challenging.