Lauinger, Ina L.; (2011) Exploring natural products for treatment and prophylaxis of Malaria. Doctoral thesis (Ph.D), University College London.

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Abstract

Malaria is the number one parasitic disease worldwide with half of the world's population at risk and nearly one million death annually. Natural products have had an enormous impact in malaria chemotherapy as the majority of current antimalarial agents are natural products or derive from a natural product scaffold isolated from plants traditionally used against malaria. The development of resistance by the deadliest parasite species Plasmodium falciparum against many antimalarial agents, including the artemisinin combinations, has become a great concern for global public health. Hence, new antimalarial drugs for chemotherapy and prophylaxis are urgently needed. Type II fatty acid biosynthesis pathway (FAS-II) has been recently shown to be indispensable for the liver stage parasites. Fatty acid biosynthesis is a crucial pathway for all living organisms as fatty acids are essential for membrane formation and energy production. Plasmodium employs type II FAS with fundamental structural and organisational differences versus the type I human FAS. This renders plasmodial FAS-II to be an excellent target for liver stage parasites and causal malaria prophylaxis. Thus, the essential FAS-II enzymes FabI, FabG and FabZ were included in the screening for new malaria prophylactic agents. One approach in the search for natural antimalarial drugs was the screening of pure natural products. Selected secondary lichen metabolites (evernic acid, vulpic acid, psoromic acid and (+)-usnic acid) were assessed for their potency against P. falciparum blood stage parasites and P.yoelii liver stage parasites, plasmodial FAS-II enzymes and their cytotoxicity. Evernic acid was identified as first natural product with potential against liver stage parasites (IC50 19.5 μM) and the FAS-II enzyme FabZ as potential target, for which it is a competitive inhibitor. Another set of natural products tested in this study were 22 selected natural chalcones, a chemical group that acts as precursors for the well-known family of flavonoids. The assessment against P. falciparum blood stage parasites identified 2',6'-dihydroy-4,4'- dimethoxydihydrochalcone as chalcone with the best antiplasmodial activity (IC50 3.7 μM), next to the known inhibitor licochalcone A (IC50 1.0 μM). In addition butein, homobutein, eriodictyolchalcone and licochalcone A were identified as promising inhibitors of the FAS- II enzyme FabZ. Structure-activity relationship studies were performed. Another approach was the screening of selected Turkish plants Anthemis cretica subsp. anatolica, Anthemis pestalozzae (Asteraceae), Salvia virgata (Lamiaceae), Scrophularia lucida and Scrophularia pinardii (Scrophulariaceae). Previous studies have shown that members of the genera Anthemis, Salvia and Scrophularia displayed significant antiplasmodial potential. Hence aerial parts and roots were extracted separately with methanol (crude extracts), which was followed by liquid-liquid partitioning and yielded the hexane, chloroform and aqueous methanol subextracts. The crude extracts and subextracts were screened for their potential against P. falciparum blood stage parasites, FAS-II enzymes and for cytotoxicity. All species showed good to moderate antiplasmodial activity and inhibition against at least one FAS-II enzyme. The aerial parts of the completely unstudied endemic Turkish plant Anthemis pestalozzae (Asteraceae) showed the most interesting profile and were selected for bioactivity-guided fractionation using a variety of chromatographic methods. Four compounds could be isolated and were identified as the cyanogenic glycoside lucumin, the benzoic acid derivative 2,6-dihydroxybenzoic acid, the indole glycoside 3-carboxymethyl-indole-l-N-β-D-glucopyranoside and a sesquiterpene lactone. The first three compounds were identified for the first time in the genus Anthemis. The sesquiterpene lactone was identified to possess the structure which was postulated for sivasinolide, however comparison of NMR data revealed significant differences. Our data suggest that the compound originally declared to be sivasinolide is very likely a different compound. In addition, the presence of the flavonoid rutin in the aqueous methanol subextract could be shown by HPLC analysis. An extensive analysis of the fatty acid composition of several fractions from the aerial parts of Antbhemis pestalozzae showed the presence of 37 different fatty acids.

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