The potential of plants as a source of anti-malarial agents Dr Geoffrey M. Rukunga Kenya Medical Research Institute PO BOX 54840 NAIROBI E-mail.

The potential of plants as a source of anti-malarial agents

Dr Geoffrey M. RukungaKenya Medical Research InstitutePO BOX 54840NAIROBIE-mail <[email protected]>

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 includesAnnonaceae LoganiaceaeMenispermaceae AsclepiadaceaeDioncophyllaceae RubiaceaRutaceae Apocynaceae

Quinine – An alkaloidal compound

5

N

HOH

NH

H

CH2

CH3O

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 includesAsteraceae SiparunaceaeCyperaceae ValerianaceaeRosaceae

Artemisinin and Mustakone

O

O

O

O

H

CH3

CH3

H

H3C

H

O

1

2

3

45

6

7

8910

11

12

13

14

15

O

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

Me

MeMe

Me

HO

O

Me

CO2MeMe

IC 50 < 200 ng/mL

Limonoids

Tetranoterpenoids a class of compounds highly active.

O

O

O

O

O

OAc

O

OCOOCH3

OO

O

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