Graduation date: 1992

Malaria is one of the three most deadly diseases in Africa. Although there are available treatments, their efficacy has been greatly reduced over the past two decades due to the development of resistance to currently available drugs. This has necessitated the search for new and effective antimalarial agents. This project approached the search for new antimalarial compounds in two ways: (i) by screening natural products isolated from marine algae against the Plasmodium parasite and (ii) by modification of selected isolated active compounds to target 1-deoxY-đ-xylulose 5-phosphate reductoisomerase (DXR), an enzyme found in the nonmevalonate isoprenoid biosynthetic pathway of Plasmodium Jalciparum. It was envisaged that such a compound would exhibit dual action on the Plasmodium parasite. Extracts obtained from 22 marine algae were prefractionated by solvent partitioning and were screened for anti plasmodial activity against the chloroquine sensitive (CQS) P. Jalciparum D 10 strain. Overall, 50% of the algae screened produced at least one crude fraction with activity against P. Jalciparum. Extracts of the algae Sargassum heterophyllum, Plocamium cornutum, Amphiroa ephedrea and Pterosiphonia cloiophylla gave the most promising results. Fractionation of S. heterophyllum afforded three tetraprenyltoluquinols (3.1, 3.2 and 3.5) and an all-trans-fucoxanthin (3.6). Three new compounds (4.5, 4.6 and 4.7) and two known halogenated monoterpenes (4.1 and 4.4) were isolated from P. cornutum. Each of the isolated compounds from both S. heterophyllum and P. cornutum showed antiplasmodial activity with IC₅₀ values ranging from 2.0 - 15.3 μM for S. heterophyllum and 13 - 230 μM for P. cornutum. Attempts to synthetically modify halogenated monoterpene 4.4 by dihydroxylation and phosphorylation in order to inhibit the DXR enzyme was unsuccessful. However, the hemiterpene analogue (5.42) of the halogenated monoterpenes was successfully phosphorylated and dihydroxylated to give compound 5.45 which showed promising activity against DXR. The result obtained indicated that the proposed phosphorylation and dihydroxylation of the halogenated monoterpene 4.4 would result in the synthesis of a potent DXR inhibitor and therefore a potential antimalarial agent with dual mode of action on the Plasmodium parasite.

Secondary metabolites from natural sources are fast growing as popular drug leads. The structural novelty and favourable biological activity that these compounds display contribute to their popularity as drugs of the future. Examples of such compounds include the potent anticancer drug paclitaxel isolated from the bark of a yew tree as well as the more commonly known analgesic aspirin which stems from the bark of the willow tree. The biological activities exhibited by these secondary metabolites are vast and range from antimicrobial to anticancer activity to mention but a few. As a result, the isolation of novel compounds from natural sources is on the rise. The South African seaboard is home to a wealth of various marine algal species which produce fascinating secondary metabolites. For example, Portierria hornemanii was shown to produce halomon, a halogenated monoterpene which has displayed promising cytotoxic activity. This study thus focused primarily on pursuing novel compounds from three endemic South African marine algal species which have never been analysed previously from a chemical perspective. These are Plocamium rigidum (Bory de Saint-Vincent), Laurencia natalensis (Kylin) and Delisea flaccida (Suhr) Papenfuss. Four known compounds and one new halogenated monoterpene, (2E,5E,7Z)-8-chloro- 7-(dichloromethyl)-4-hydroxy-3-methylocta-2,5,7-trienal, were isolated from Plocamium rigidum. The breast cancer (MCF-7 cell line) inhibitory activity for these compounds was assessed and it was observed that an increase in the lipophilic nature of the compounds produced more favourable IC50 values. A pre-cursor to bromofucin type compounds, cis-laurencenyne, was isolated from Laurencia natalensis, as well as a new acetoxy chamigrane type compound, 4-bromo- 3,10-dichloro-7-hydroxy-3,7,11,11-tetramethylspiro [6.6] undec-1-yl acetate. Delisea flaccida was seen to contain two known bromofuranone type compounds isolated as an isomeric mixture, 1-[(5Z)-4-bromo-5-(bromomethylidene)-2-oxo-2,5- dihydrofuran-3-yl] butyl acetate and 1-[(5E)-4-bromo-5-(bromomethylidene)-2- oxo-2,5-dihydrofuran-3-yl]butyl acetate. These compounds are famous for their ability to inhibit bacterial biofilm production and they have been isolated before from an Australian Delisea spp / Adobe Acrobat 9.53 Paper Capture Plug-in