Part A: Antimalarial agents modified at the C-16 position of artemisinin; Part B: Lead optimization of falcipain-2 and falcipain-3 inhibitors
Date of Award
Ph.D. in Pharmaceutical Sciences
Mitchell A. Avery
John M. Rimoldi
Part A: Antimalarial Agents modified at the C-16 position of Artemisinin. Malaria is a widespread tropical and subtropical parasitic disease which is caused by malarial parasites and transmitted by the infected anopheles mosquitoe. The natural product artemisinin and its derivatives are currently considered the most effective drugs against drug resistant plasmodium falciparum. However, its undesired physicochemical proprieties have limited its usage. In order to improve its effectiveness, scientists around the world have developed novel methodology to synthesize artemisinin derivatives on different positions of the artemisinin skeleton. Previous work in our group has shown that many analogues modified at the C-16 of artemisinin had improved efficacy along with modified physicochemical proprieties. This work focuses on the synthesis of heteroatomic and heterocyclic derivatives of artemisinin with the emphasis on C-16 substituted triazole containing side-chains. Successful synthetic results and subsequent bioassay demonstrated that the compounds have modest antimalarial activity compared to artemisinin and improved water solubility. With these encouraging results in hand, further work is underway to tune the desired physicochemical properties so that plasma half-life and oral bioavailability will be improved. Part B: Lead Optimization of Falcipain-2 and Falcipain-3 Inhibitors. The expanding usage of artemisinin combination therapy casts concern about the potential development of drug resistance to this drug family, thus the search for new drug targets is always needed. Falcipain-2 (FP-II) and falcipain-3 (FP-III) are two cysteine proteases which malarial parasites utilize to degrade hemoglobin to obtain amino acids essential to the parasite. The inhibition of these two enzymes has been shown to have deadly effects on the protozoan life cycle. Recently published crystal structures of FP-II provided an outstanding opportunity for rational drug design and discovery. In the present study, structure-based optimization of virtual screening hits was carried out using scaffold hopping, docking and analogue synthesis. Unfortunately, the biological evaluation of the synthesized compounds against FP-II and FP-III indicated these compounds are inactive. However, the information gained from this exercise could aid further in optimization of this series of compounds.
Wu, Yunshan, "Part A: Antimalarial agents modified at the C-16 position of artemisinin; Part B: Lead optimization of falcipain-2 and falcipain-3 inhibitors" (2013). Electronic Theses and Dissertations. 1451.
Emphasis: Medicinal Chemistry