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Artemisinin Derivatives to Fight Malaria

   Faculty of Science

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

A self-funded PhD position is available in the Fielding and Ismail research groups. We investigate unpaired electron species that play an important role in biological and materials chemistry. In recent years we have worked on the design and characterization of several novel antimalarials to understand their mechanism of action.1-3

Malaria is caused by protozoan parasites of the genus Plasmodium and is a major cause of mortality and morbidity worldwide. These parasites have a complex life cycle in their mosquito vector and vertebrate hosts. The primary factors contributing to the resurgence of malaria are the appearance of drug-resistant strains of the parasite, the spread of insecticide-resistant strains of the mosquito and the lack of malaria vaccines of high proven efficacy. While the world's focus has been on COVID-19, 14 million new cases of malaria emerged in 2020, and the number of cases and deaths in the 2021 WHO World Malaria report are the highest since 2012.

Artemisinin is a sesquiterpene lactone bearing an unusual peroxide bridge. Artemisinin-based combination therapies are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine. It’s discovery received the 2015 Nobel Prize in Physiology or Medicine. Despite the efforts dedicated to its unravelling, the mechanism of action of artemisinin has not yet been elucidated beyond the fact that the presence of the 1,2,4-trioxane ring is an essential feature of its pharmacological activity. The presence of the endo-peroxidic group within the 1,2,4-trioxane moiety along with the presence of transition metal ions [e.g. Fe(II)] in the biological medium suggests that the activity of artemisinin may take place via radical processes triggered by the electron-transfer (ET)-induced cleavage of the endo-peroxidic bond. Studies have also reported a viable therapeutic strategy of using artemisinin in combination with antioxidants, which was aimed at alleviating plasmodium-induced oxidative stress and its associated complications. Consequently, there is a need for mechanistic understanding to guide drug design towards more effective treatments.

Our research is currently investigating novel artemisinin derivatives. The project is interdisciplinary and collaborative, and, together, we would design the experiments around your skills and what you would like to learn. This could involve synthetic organic chemistry, nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography and computational chemistry. You would also experience the wonderful city of Liverpool.

Informal inquiries can be made to:

1.          Kelly-Hunt, A.E., Mehan, A., Brooks, S., Leanca, M.A., McKay, J.E.D., Mahamed, N., Lambert, D., Dempster, N.M., Allen, R.J., Evans, A.R., Sarker, S.D., Nahar, L., Sharples, G.P., Drew, M.G.B., Fielding, A.J.*, and Ismail F.M.D.*, Synthesis and Analytical Characterization of Purpurogallin: A Pharmacologically Active Constituent of Oak Galls, J. Chem. Educ. 2022, 99, 2, 983–993.

2.      Del Casino A., Luković, V., Bhatt, R., Randle, L.E., Dascombe, M.J., Fennell, B.J., Drew, M.G.B., Bell, A.B., Fielding, A.J.*, Ismail*, Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials, ChemistrySelect 2018, 3, 7572-7580.

3.     Fielding, A.J.*, Luković, V., Evans, P.G., Alizadeh-Shekalgourabi, S., Bisby, R.H., Drew, M.G.B, Del Casino, A., Dunn, J.F., Randle, L.E., Dempster, N.M., Dascombe, M.J., Ismail, F.M.D*, Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor in vivo Using Fluorinated Bisquinolines, Chemistry – A European Journal 2017, 23, 6811-6828.

See also https://www.ljmu.ac.uk/about-us/staff-profiles/faculty-of-science/pharmacy-and-biomolecular-sciences/alistair-fielding and https://www.ljmu.ac.uk/about-us/staff-profiles/faculty-of-science/pharmacy-and-biomolecular-sciences/fyaz-ismail for further details on current research and a full list of recent publications.

Funding Notes

This is a self-funded PhD project for students with their own funding/scholarship. Please see our website for 2021/22 tuition fee information: View Website. 2022/23 fees are yet to be confirmed and will be included on this section of the website, in due course.

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