Antimalarial Activity of Cantharidin Analogs: Potential Serine/Threonine Protein Phosphatase Inhibitors

Cantharidin is a natural toxin isolated from blister beetle. Chinese have used this compound as a drug since the 13th century. Cantharidin has been utilized as a medicine against hepatoma and oesophageal carcinoma [1]. Medicinal interest in this compound has continued until the present. Cantharidin is an analog of endothall, a dicarboxylic acid herbicide, which has shown the best in vitro antiplasmodial activity among the commercial herbicides that we tested previously [2]. This compound inhibits protein phosphatases (PP1 and PP2A) from mammals and plants [3,4]. Recent studies have shown that the function of enzyme PP1 is essential for P. falciparum during release of mature merozoits from erythrocytes [5]. Protein phosphatases play important roles in signal transduction pathways and together with kinases maintain a delicate balance between phosphorylated and dephosphorylated forms of certain proteins. In this manner they regulate gene expression, cellular proliferation, cell differentiation and apoptosis [6]. Recently, extensive studies have been done on synthesis of several novel cantharidin analogs. The primary objective has been to obtain the analogs with improved efficacy and better specificity. In this study, we have determined IC₅₀ of 81 different cantharidin analogues against chloroquine-susceptible (D6) and -resistant (W2) strains of Plasmodium falciparum. Most compounds were less active than cantharidin (IC₅₀ D6 9 ± 0.8 and W2 9 ± 0 µM, respectively) and endotall (IC₅₀ D6 7.8 ± 0.4 and W2 8 ± 0 µM, respectively). Seven compounds showed in vitro antimalarial activity similar or greater than cantharidin. Only one compound was three-fold more active than cantharidin (IC₅₀ D6 3 ± 0 and W2 3 ± 0.8 µM). The antimalarial activity of cantharidin maybe improved by alteration of its chemical structure. The studies indicate serine/theronine protein phosphates as a potential antimalarial drug target and also provide directions for future modifications of cantharidin for new antimalarial drug discovery. References: [1] Nicholls LC, Teare, D (1954) Br J Med. 2: 1384–1386. [2] Bajsa J, Singh K (2007) Biol. Pharm. Bull. 30: 1740–1744. [3] Ayaydin F, Vissi E (2000) Plant J. 23: 85–96. [4] Li Y, Casida J (1992) Proc. Natl. Acad. Sci. U.S.A. 89: 11867–11870. [5] Blisnick T, Vincensini L (2006) Cell Microbiol. 8: 591–601 [6] Kessler F, Schnell DJ (2006) Traffic 7: 248–257.