Submitted to: Bioorganic and Medicinal Chemistry Letters
Publication Type: Peer reviewed journal
Publication Acceptance Date: 9/1/2010
Publication Date: 11/15/2010
Citation: Bajsa, J.N., Mccluskey, A., Gordon, C.P., Stewart, S.G., Hill, T.A., Sahu, R., Duke, S.O., Tekwani, B.L. 2010. The antiplasmodial activity of norcantharidin analogs. Bioorganic and Medicinal Chemistry Letters. 20(22):6688-6695. Interpretive Summary: Malaria is still a dangerous disease, despite the availability of antimalarial drug. This situation is partly caused by the high ability of Plasmodium falciparum to evolve resistance to the most commonly used drugs during the constant selection pressure. Therefore there is an urgent need of new drug development against new enzyme targets of this protozoan parasite. At least two features of norcantharidin analogues make them a potential source of antimalarials. First, their well known targets are serine/threonine protein phosphatases, enzymes that are not targets of any commercial antimalarials. Second, these enzymes play crucial roles in the Plasmodium falciparum life cycle. Sixty norcantharidin analogues were tested. Most chemical modifications caused reduction in activity below that of cantharidin. Three of them had similar or greater activity than cantharidin.
Technical Abstract: Despite the availability of many antimalarial drugs, including chloroquine (CQ), artemisinin, atovaquone, proguanil and sulphadoxine-pyrimethamine (SP), malaria remains a serious disease. Malaria is especially dangerous due to the ability of Plasmodium falciparum to evolve resistance to the most commonly used drugs during the constant selection pressure. Therefore, there is an urgent need for new drug development targeting this protozoan parasite. At least two features of norcantharidin analogs make them a potential source of antimalarials. Firstly, they target serine/threonine protein phosphatases. These enzymes are not the targets of any of the current commercial antimalarials. Secondly, these enzymes play crucial roles in the Plasmodium falciparum life cycle and are potential drug targets. The antiplasmodial activities of norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum using the parasite lactate dehydrogenase (pLDH) assay. 60 norcantharidin analogs were tested. Most of the chemical modifications caused reduction in antiplasmodial activity below that of cantharidin, the lead compound. Three of them had similar or greater activity than cantharidin. 3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid, compound B005, was 3-fold more active than cantharidin (IC50 D6 3 ±0 , W2 3.0 ± 0.8 µM v/s D6 9 ± 0.8, W2 9 ± 0 µM). The antimalarial activity of cantharidin can be improved by alteration of its chemical structure. These results provide directions for future modifications of cantharidin.