Identification, Structure-Activity Relationship (SAR), and Biological Evaluation of New Chemical Series as Malaria Parasite GCN5 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 GCN5. From the 6 initial hits with pIC > 5, two compounds were progressed for further profiling and optimization. Computational and medicinal chemistry efforts delivered significantly improved compounds and with pIC within the submicromolar range (pIC 6.6 and 7.0, respectively), but unfortunately, the lead compounds did not show potent antiparasitic activity. Although further studies are still necessary, our initial data suggest that targeting GCN5 to develop new antimalarial compounds might be challenging.