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Abstract
Malaria is a deadly infectious disease, which threatens nearly half of the global population. Although it has been eliminated in much of the developed world, it remains a public health challenge to impoverished and developing countries. A major impediment in the elimination of malaria globally is the presence of drug resistance to all currently available antimalarial therapies, creating the need for continued research into the next generation of antimalarial therapies with novel structures and mechanisms of action. This dissertation addresses the continued need of drug discovery for malaria using recently identified potent antimalarials from natural sources. Across three studies, antimalarial mechanisms of resistance and mode of action are identified for a small collection of lindenane sesquiterpenoid dimers from Chloranthacae spp. plants and two alkaloids from Crinum erubescens. The identification of these mechanisms can be leveraged to further preclinical development of these small molecules as well as to identify or rationally design antiplasmodial compounds with the aim of developing new therapeutics to assist in the World Health Organization (WHO) goal to eliminate Malaria by 2030.