Mycetoma is an infectious neglected tropical disease of skin and subcutaneous tissues caused either by bacteria (actinomycetoma) or a fungus (eumycetoma). The fungal subtype is usually caused by the Madurella genus, with Madurella mycetomatis being the most prevalent. The complex nature of the mycotic disease is characterised by a clinical triad which involves the ability of the fungal pathogen to form grains, sinuses within nodules and subcutaneous tumours. Current treatment therapies, apart from not being effective (25–35% cure rates) and target specific, are extremely expensive and therefore put a large financial burden on the impacted local citizens within the endemic mycetoma belt countries, where the disease is geographically prevalent. In response to the ongoing demand for alternative and effective treatment methods, and the lack of commercial incentives for the pharmaceutical industry to develop them, the Open Source Mycetoma (MycetOS) project was launched in 2017 with the aim of discovering new molecules against the disease. Guided by six defining principles, the open source approach addresses the problem using a collaborative effort in which all data are shared, anyone may participate and no patents are taken. At the start of the project, a focused library screening of 800 chemical entities led to the discovery of an active molecule based on a fenarimol core. This thesis describes the medicinal chemistry campaign that was carried out to improve this molecule and understand the relevant structure–activity relationship. The project was diversified by the identification of a new series based on a ketoxime scaffold. Both in vitro and in vivo susceptibility assays have established a direct correlation between lipophilicity (logD) and compound potency against the mycotic pathogen, which will be an important physicochemical consideration in the future planning of both series. The thesis concludes with i) the separation of ketoxime diastereomers and experiments related to their interconversion and ii) comments on future directions for the medicinal chemistry campaigns.
LA - ENG M3 - PhD Thesis N2 -Mycetoma is an infectious neglected tropical disease of skin and subcutaneous tissues caused either by bacteria (actinomycetoma) or a fungus (eumycetoma). The fungal subtype is usually caused by the Madurella genus, with Madurella mycetomatis being the most prevalent. The complex nature of the mycotic disease is characterised by a clinical triad which involves the ability of the fungal pathogen to form grains, sinuses within nodules and subcutaneous tumours. Current treatment therapies, apart from not being effective (25–35% cure rates) and target specific, are extremely expensive and therefore put a large financial burden on the impacted local citizens within the endemic mycetoma belt countries, where the disease is geographically prevalent. In response to the ongoing demand for alternative and effective treatment methods, and the lack of commercial incentives for the pharmaceutical industry to develop them, the Open Source Mycetoma (MycetOS) project was launched in 2017 with the aim of discovering new molecules against the disease. Guided by six defining principles, the open source approach addresses the problem using a collaborative effort in which all data are shared, anyone may participate and no patents are taken. At the start of the project, a focused library screening of 800 chemical entities led to the discovery of an active molecule based on a fenarimol core. This thesis describes the medicinal chemistry campaign that was carried out to improve this molecule and understand the relevant structure–activity relationship. The project was diversified by the identification of a new series based on a ketoxime scaffold. Both in vitro and in vivo susceptibility assays have established a direct correlation between lipophilicity (logD) and compound potency against the mycotic pathogen, which will be an important physicochemical consideration in the future planning of both series. The thesis concludes with i) the separation of ketoxime diastereomers and experiments related to their interconversion and ii) comments on future directions for the medicinal chemistry campaigns.
PB - University College London PY - 2024 TI - Open Source Mycetoma (MycetOS): Discovery and Development of Antifungal Agents Against the Neglected Mycotic Disease ER -