Antimalarial drug interactions of compounds isolated from Kigelia africana (Bignoniaceae) and their synergism with artemether, against the multidrug-resistant W2mef Plasmodium falciparum strain

For decades, drug resistance has been the major obstacle in the fight against malaria, and the search for new drugs together with the combination therapy constitutes the major approach in responding to this situation. The present study aims at assessing the in vitro antimalarial activity of four compounds isolated from Kigelia africana stem bark (atranorin - KAE1, specicoside - KAE7, 2 beta,3 beta,19 alpha-trihydroxy-urs-12-20-en-28-oic acid -aEuro parts per thousand KAE3, and p-hydroxy-cinnamic acid -aEuro parts per thousand KAE10) and their drug interactions among themselves and their combination effects with quinine and artemether. The antiplasmodial activity and drug interactions were evaluated against the multidrug-resistant W2mef strain of Plasmodium falciparum using the parasite lactate dehydrogenase assay. Three of the four compounds tested were significantly active against W2mef: specicoside (IC50 = 1.02 +/- 0.17 mu M), 2 beta,3 beta,19 alpha-trihydroxy-urs-12-en-28-oic acid (IC50 = 1.86 +/- 0.15 mu M) and atranorin (IC50 = 1.78 +/- 0.18 mu M), whereas p-hydroxy-cinnamic acid showed a weak activity (IC50 = 12.89 +/- 0.87 mu M). A slight synergistic effect was observed between atranorin and 2 beta,3 beta,19 alpha-trihydroxy-urs-12-en-28-oic acid (Combination index, CI = 0.82) whereas the interaction between specicoside and p-hydroxy-cinnamic acid were instead antagonistic (CI = 2.67). All the three compounds showed synergistic effects with artemether, unlike the slight antagonistic interactions of atranorin and 2 beta,3 beta,19 alpha-trihydroxy-urs-12-en-28-oic acid in combination with quinine. K. africana compounds are therefore likely to serve as leads in the development of new partner drugs in artemether-based combination therapy.