Antiplasmodial activity of abietane diterpenes isolated from five southern African Plectranthus species

The emergence of drug-resistant strains of Plasmodium falciparum has resulted in an urgent need to develop new antimalarial chemotherapeutic agents. The rich plant diversity and long history of traditional medicine in southern Africa warrants investigation and may be a valuable source of novel compounds. Plectranthus species were investigated based on their association with the treatment of „fever“, which could be due to a „malarial or febrile condition“. Seven known abietane diterpenes have been isolated in pure form from the leaves of five indigenous Plectranthus species, namely P. hadiensis, P. lucidus, P. ecklonii, P. purpuratus subsp. purpuratus and P. purpuratus subsp. tongaensis. The seven compounds were tested for antimalarial activity against the intra-erythrocytic stage of the chloroquine-resistant strain of P. falciparum (FCR-3) using the [³H]-hypoxanthine incorporation assay. Their ability to inhibit β-haematin formation was performed at acidic conditions as in the parasite food vacuole. The toxicity profiles were determined using the tetrazolium cell proliferation assay against human kidney epithelial cells. Overall, the compounds displayed good antiplasmodial activity (IC₅₀ values ranging from 3.11 to 14.65µM), with compound 4 (11-hydroxy-2α-(3,4-dihydroxybenzoyloxy)abieta-5,7,9(11),13-tetraene-12-one) being 62% as effective as chloroquine in inhibiting β-haematin formation. However, the cytotoxicity profile indicated a low degree of specificity towards the malaria parasite. When combined with quinine, compounds 4, 5 (11-hydroxy-19-(methyl-buten-2-oyloxy)-abieta-5,7,9 (11),13-tetraene-12-one), and 7 (11-hydroxy-19-(3,4-dihydroxybenzoyloxy)-abieta-5,7,9(11),13-tetraene-12-one) interacted in an additive manner; while compound 1 (7α-formyloxy-6β,12-dihydroxy-abieta-8,12-diene-11,14-dione) interacted synergistically. Further chemical modifications of these naturally-derived compounds could yield more active antiprotozoal agents with decreased toxicity.

Acknowlegements: National Research Foundation (South Africa); University Research Committee (University of KwaZulu-Natal).