Anti-malarial compounds and cocrystals based on 11-azaartemisinin

Abstract

Artemisinin combination therapies (ACT) are considered currently the most effective way to treat malaria, a disease affecting millions of people worldwide. However, recent reports display the drastic emerging resistance to ACTs in South East Asia which highlight the need for new anti-malarial drugs. The rapid mode of action of artemisinin in the reduction of parasitemia suggests that the new artemisinin derivative, selected to be used in ACTs, should have higher thermal stability, less neurotoxicity and must not convert to dihydroartemisinin (DHA) in a metabolic pathway. 11-Azaartemisinin (11-Aza) and its derivatives are compounds of pharmaceutical interest since they are active against drug-resistant malarial parasites and do not change to DHA. In this research work, chapter 2 describes the preparation of a number of 11-Aza derivatives and their characterization by proton and ¹³C NMR, MS, TGA, and DSC. Single crystal XRD studies of these compounds are also performed to understand their solid state packing arrangements. Furthermore, the potential for 11-Aza derivatives to form quasi-polymorphs has also been explored, explaining how and why their structures are different. Attempts to use hetero-crystal seeding to grow real polymorphs for some of these compounds have been made. These principles could be applied as an approach to otherwise inaccessible solid-state forms of many drugs, or indeed organic compounds in general. 11-Aza has also been found to readily form cocrystals compared to its parent compound, artemisinin. In chapter 3, cocrystal formation of 11-Aza with some common organic acids is explored, whereas chapter 4 expands the cocrystallization studies of 11-Aza with other cocrystal formers such as other anti-malarial drugs, alcohols, and sugars. 13 new 1:1 and 2:1 cocrystal phases from 25 mono- and bi-functional acids are obtained in excellent yield and purity by liquid-assisted grinding. X-ray structures of several of these cocrystals reveal R²₂(8) heterosynthons with short OH┄O=C H-bonds ≤2.60 Å between the 11-Aza lactam and the coformer acid groups. In the case of drug-drug cocrystallizations, 11-Aza cocrystal with rac-mefloquine hydrochloride appeared to be the most successful one. Chapter 5 discusses the biological activity assay, thermal studies, stress testing and, dissolution studies performed on 11-Aza cocrystals and derivatives. Antimalarial activities are measured in vitro against asexual and sexual stages of drug-resistant and drug-sensitive strains of Plasmodium falciparum parasite. It was discovered that 11-Aza compounds display antiplasmodial activities greater than or equal to the reference drugs. Moreover, 11-Aza compounds show greatly enhanced thermal stability. Also, the cocrystal phases can show enhanced aqueous solubility and dissolution rate. Apart from this, the crystal structure of 11-Aza and another artemisinin analog, Artemisone, is studied at low and room temperatures. Artemisone exhibits a phase transition behavior at different temperature conditions. To date, the artemisone structure has only been reported at low-temperature XRD study. Since artemisone is a potential antimalarial drug candidate and passed the phase I of its clinical trials, it is crucial to understand its solid state stability at different temperatures and studying its phase transition behavior can provide information on it which has been discussed at the end of chapter 5. Chapter 6 describes the summary of the previous chapters, the impact of this research as well as some future research prospects.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology