C-7 Functionalization and Preparation of Analogues of Artemisinin

Date of Degree


Document Type


Degree Name

Master of Science (MS)


Pharmaceutical Sciences


Paulo B. Carvalho


Karen G. Le Roch


Russell W. Raymond


Raghunandan Yendapally


While malaria has been around for centuries, there is yet to be a cure. An estimated US $15 billion was raised by the Global Fund, which fell short of the 2022 goal of US $18 billion, in the efforts to control malaria with no end in sight. The human burden is also enormous, as malaria impacts 3.3 billion people in over 100 of the most impoverished countries annually and over a half a million people die each year, the majority being children under the age of five. Currently, artemisinin is the gold standard for the treatment of malaria used in conjunction with other therapeutics, but there have been reports of the parasite Plasmodium falciparum being partially resistant to the effects of artemisinin in the Greater Mekong subregion of southeast Asia. Furthermore, the most current malaria report from the World Health Organization reports partial artemisinin resistance in the WHO African region which has not originated from the Greater Mekong subregion. Due to the heavy reliance on artemisinin combination therapies in these regions there is a great need for improvement to these therapies. In an effort to develop new anti-malarial therapies we subjected artemisinin to a known biotransformation by Cunninghamella elegans 9245 in order to activate carbon number 7 on its structure for the preparation of a totally new set of derivatives. Biotransformation reactions are notoriously low-yielding processes, and, by conducting a multi-factorial study that involved manipulating pH, spin rate, morphology of the initial fungal inoculate, as well streamlining the work-up process, yields were improved by up to 15% for a total yield of 35% of the desired C-7 hydroxy metabolite on average. This highly valuable metabolite served as the key intermediate for our medicinal chemistry campaign which sought to improve the biological activity and favorable physicochemical properties associated with artemisinin through a series of iterative drug design cycles. Preliminary results from our studies show improved anti-malarial activity, which could translate potentially into the development of a novel artemisinin derivative for better therapy, which could combat the emerging number of drug resistant cases reported in the medical literature.

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