ABSTRACT
Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria.
Subject(s)
Antimalarials/toxicity , Embryo, Mammalian/drug effects , Embryo, Mammalian/pathology , Teratogens/toxicity , Tetraoxanes/toxicity , Animals , Antimalarials/chemistry , Artemisinins/chemistry , Artemisinins/toxicity , Artesunate , Caspases/metabolism , Cell Death/drug effects , Cell Line , Female , Heme/metabolism , Humans , Iron/metabolism , Male , Oxidative Stress/drug effects , Plasmodium falciparum/drug effects , Rats , Rats, Sprague-Dawley , Spiro Compounds/chemistry , Spiro Compounds/toxicity , Tetraoxanes/chemistry , Time FactorsABSTRACT
Substituted tetraoxanes with different substitution pattern on the aromatic ring were synthesized in order to explore the influence of different substituents in the antimalarial activity. Antimalarial activity of these compounds improves by the introduction of ethyl, iso-propyl or n-propyl groups in the aromatic ring but substitution with n-butyl or t-butyl leads decrease in antimalarial activity. Some of these compounds exhibit promising antimalarial activity. None of the compounds shows any toxicity against vero cells and three compounds (2a-2c) were tested against panel of six cell lines and none of these compounds showed any toxicity. X-ray crystal structure of compound 2w showed that tetraoxane ring is in the chair conformation with both the phenyl rings in the equatorial position. In addition, FeCl(3) mediated O-O bond scission of tetraoxanes (2a-2c) was also examined.
