Synthesis and Evaluation of Anti-Malarial Compounds Based On an Open Source Lead
Embargoed until: 2019-12-05
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Malaria infection is still considered a major global health problem. According to the WHO World Malaria Report 2017, 91 countries reported a total of 216 million cases of malaria in 2016, an increase of 5 million cases over 2015. Furthermore, the global malaria deaths in 2016 reached 445,000 deaths, which is approximately same number as was reported in 2015. There is a pressing need for new drugs because multiple drug resistance now exists, including artemisinin and various partner drugs. Owing to this situation, this MSc project focused on the potentially lead optimization of a spirochromanone compound (MMV085230) which constituted part of the Medicines for Malaria Venture Pathogen Box. This unique source contains 400 diverse and drug-like molecules that are classified as open source. The Msc project aimed to synthesise analogues of MMV085230, fully characterise these compounds by spectroscopy methods, then test all analogues for in vitro antimalarial activity and analyse data for structure-activity relationships. Using 2-hydroxyacetophenone and its derivatives to react with 1-Boc-4-piperidone, various spirochromanes were formed. Following deprotection of the chromanone a number of isocyanates were used to synthesize a variety of ureas spirochromanone analogues. Furthermore, three spriochromanone allyl ureas were hydrogenated to give desired compounds. By using spectroscopy (NMR and MS) and chromatography (flash column and HPLC) techniques, twelve pure compounds were acquired for biological testing.
Master of Science (MSc)
School of Environment and Sc
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Malaria Venture Pathogen Box