The potential of plants as a source of anti-malarial agents Dr Geoffrey M. Rukunga Kenya Medical Research Institute PO BOX NAIROBI

Global statistics of Malaria  1.5 – 2.7 million deaths annually  Over 1 billion clinical episodes  300 – 500 million people infected  Every 10 – 30 seconds a child dies of malaria

Impact of malaria in Africa  Major health problem in the tropics  About 90 million clinical cases annually.  Malaria leads to economic loss.  Most affected are pregnant women and children Under 5 years.

What contributes to the problem?  Resistance to conventional drugs.  Affordability of available drugs. There for need to continue searching for new agents

Plant drugs  Approximately 80% of the people in the developing countries depend on traditional medicine.  The discovery of quinine and artemisinin has stimulated interest in medicinal plants as sources of new antimalarial drugs.

Selection of plants for antimalarial activity  Ethno medical bases  Random selection

Methodologies  Extractions – water or organic solvent  In vitro assays – IC 50s  Cytotoxicity assays CC50’s  Selectivity index (S.I) = IC 50/CC50  In vivo assays – percentage chemosuppression of parasitaemia.  Toxicity in animals.  Activity guided isolation of the active compound (?)

So many publications yet few candidates anti-malarial agents  Anti-malarial compounds rare.  Most studies ends up with only in vitro assays.  If beyond in vitro assay – then toxicity - problem  Usually because of lack of resources - trained personnel - equipment - Finances

Categorization of plants extracts with in vitro anti-plasmodial activity  Category 1: High activity IC 50 equal or less than 10  g/mL  Category 2: Moderate activity IC 50 between 10 and 100  g/mL  Category 3: Low or no activity IC 50 Above 100  g/mL

Category 1 (High activities) 120 plant extracts from 74 plant species, belonging to 34 families. Some of the families with more species than others: Annonaceae (alkaloids) Apocynaceae (Alkaloids) Asteracea (sesquiterpenes) Celestraceae (Triterpenes) Meliaceae (limonoids) Simaroubaceae (quassinoids) Menispermaceae (Alkaloids) Rutaceae (Alkaloids) Rubiaceae (alkaloids)

Category 2 – moderate activities 203 plant extracts from 129 plant species, belonging to 50 families. Some of the families with more species than others: Annonaceae Asteraceae Meliaceae Loganiacea Fabaceae

Classes of compounds with high anti-malarial activities Alkaloids  Basic compounds -highly bioactive compounds.  The structures are very diverse  Families containing the compounds includes AnnonaceaeLoganiaceae MenispermaceaeAsclepiadaceae Dioncophyllaceae Rubiacea Rutaceae Apocynaceae

Quinine – An alkaloidal compound

Quassinoids  Heavily oxygenated lactones majority with C-20 basic skeleton.  The structures are very diverse  Simaroubaceae – is the family associated with quassinoids

A quassinoid from Simaba guianensis (Simaroubaceae) IC 50 < 1.7 ng/mL

Sesquiterpenes  Biosynthetically made from three 5-carbon isoprene units skeleton  Among the most active terpenoids  Artemisinin belongs to thisd class of compounds.  Families identified with highly active sesquiterpenes includes AsteraceaeSiparunaceae CyperaceaeValerianaceae Rosaceae

Artemisinin and Mustakone

Triterpenes Triterpenes.  Biosynthetically made from 6 units isoprene units  Diverse sructures. Some triterpenes have exhibited high anti-plasmodial activity. Families associated includes: -Ancistrocladaceae - Meliaceae - Simaroubaceae - Celestraceae

pristimerin – triterpene from Maytenus senegalensis - Celestraceae IC 50 < 200 ng/mL

Limonoids Tetranoterpenoids a class of compounds highly active. IC 50s < 1ug/mL Family associated with these compounds – Meliaceae

Discussions Points to consider in the categorization of the plant extracts with anti-plasmodial activity.  Type of extract  Strain of Plasmodium parasite used in the assay  Part of the plant extracted  Geographical location of plant  Time of the year harvested  Thus categorization is a guide

Way forward Prioritization of plants as source of anti-malarial agents.  Families whose exts have high anti-malarial activity (cat 1&2).  Families that contain class of compounds with known potent anti-malarial activity e.g liminoids, alkaloids, quassinoids etc.  Cytotoxicity after in vitro anti-plasmodial assays.  Confirm activity in vivo  Toxicity studies in animals.  plant part: leaves > stems > roots  Ease of propagation, cultivation etc  Team work – the only answer.

End Thank you