Kouipou, R. M. T. | bioRxiv Science

bioRxiv2025

Discovery and structure-activity relationship analysis of 2-Pyridyl Thienopyrimidine derivatives as promising therapeutic candidates for the treatment of Buruli ulcer

Mycobacterium ulcerans, the bacterium causing Buruli ulcer (BU), can potentially develop resistance to existing antibiotics (rifampicin - clarithromycin/ moxifloxacin), underscoring the need for new antimycobacterial treatments. This study screened the Pathogen Box from Medicines for Malaria Venture (MMV) to identify M. ulcerans inhibitors. Four hit compounds were found, including the 2-(6-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV688122 as a novel anti-M. ulcerans chemotype. Synthesis of structural analogues of MMV688122 allowed the identification of 2-(4-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV1578877 as the most potent, with submicromolar activity. Importantly, this analogue was non-cytotoxic up to 100 {micro}M in human fibroblasts. Structure-activity relationship (SAR) studies indicated the crucial role of the methylpyridin-2-yl group in inhibiting M. ulcerans and the possibility to replace the thienopyrimidine core by a quinazoline. While MMV1578877 showed better metabolic stability than MMV688122, further improvement and testing in real-world M. ulcerans clinical isolates are still required. Further metabolite identification and SAR data should guide the optimization of this novel chemotype to enable in vivo testing. Author SummaryBuruli ulcer is a neglected tropical disease that causes severe skin ulcers and long-term disability, mostly affecting people in remote African communities. Current treatments rely on antibiotics that are not always effective and may lead to resistance. In this study, we searched for new drug candidates by testing a library of compounds provided by the Medicines for Malaria Venture (MMV). We discovered a promising new chemical family that can kill the bacteria responsible for Buruli ulcer in the lab. One compound, in particular, showed strong activity without harming human cells. This compound also showed better stability and effectiveness. These findings bring us closer to developing a new, safer, and more effective treatment for Buruli ulcer.

pharmacology and toxicology↗

bioRxiv2019

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.

pharmacology and toxicology↗