Screening the MMV Open Access Pathogen box unveils novel and potent inhibitors of Amoebiasis agent: Entamoeba histolytica

Amoebiasis caused by the protozoan parasite Entamoeba histolytica remains a major public health hazard, as being the second cause of death among parasitic infections. Although currently prescribed drugs have shown to be effective in the treatment of amoebiasis, side effects and emergence of parasites resistance prompted the search for novel drug to control this disease. In this regard, the Medicines for Malaria Venture (MMV) Pathogen Box library of selected compounds was screened to identify anti-Entamoeba histolytica agents using the resazurin based fluorescence assay. Overall, the results revealed three novel anti-Entamoeba histolytica scaffolds with low micromolar activity including MMV675968 (IC50 = 2.10 {micro}M), MMV688179 (IC50 = 2.38 {micro}M) and MMV688844 (IC50 = 5.63 {micro}M). Structure-Activity-Relationship (SAR) studies led to identification of two analogs [~]100 fold more potent and selective than the original hit compound 1 (MMV675968): 1k (IC50 = 0.043 {micro}M) and 1l (IC50 = 0.055 {micro}M). Predictive analysis using Maestro 11.6 suggested that these hit compounds possess acceptable physicochemical and metabolism properties. These lead compounds are therefore good starting points for lead optimization studies towards identification of drug candidate against amoebiasis.\n\nAuthor SummaryDiarrhoea is a leading cause of death for millions of children worldwide. One of the top 15 causes of severe diarrhoea is Entamoeba histolytica, causing amoebiasis. What makes E. histolytica dangerous is its ability to disseminate easily through a given population via contaminated food and water supplies. Moreover, E. histolytica is quite comfortable in the environment, difficult to kill with chorine and infect people at a very low dose, making it a priority pathogen to eradicate. Many drugs have been developed so far to cure this infection. However, they are not efficient enough to control the disease due to pathogen resistance that is becoming a big issue. In addition to that, almost all the drugs in use are highly toxic to human causing several side effects upon medications. Therefore, new, more efficient and less toxic drugs are urgently needed for the better management of amoebiasis. Since the development of a new drug takes years, repurposing existing drugs has been shown to shortcut the process and boost the discovery rate of new medicines. Using this same approach, we have identified two compounds that potently inhibit E. histolytica and are nontoxic that can enter the drug discovery pipeline for new amoebicidal drug development. Moreover, these new inhibitors could also serve as starting points for the synthesis of a library of amoebicidal compounds.