arterolane and artemisinin

Recently published data suggest that artemisinin derivatives and synthetic peroxides, such as the ozonides OZ277 and OZ439, have a similar mode of action. Here the cross-resistance of OZ277 and OZ439 and four additional next-generation ozonides was probed against the artemisinin-resistant clinical isolate Plasmodium falciparum Cam3.I, which carries the K13-propeller mutation R539T (Cam3.I. The previously described in vitro ring-stage survival assay (RSA. At the pharmacologically relevant concentration of 700 nM, all six ozonides were highly effective against the dihydroartemisinin-resistant P. falciparum Cam3.I. The absence of in vitro cross-resistance against the artemisinin-resistant clinical isolate Cam3.I

Topics: Adamantane; Antimalarials; Artemisinins; Drug Resistance; Heterocyclic Compounds, 1-Ring; Peroxides; Plasmodium falciparum; Spiro Compounds

The ring-stage susceptibility assay was modified to quantify the susceptibilities of multiple strains of control and delayed-clearance phenotype (DCP) Plasmodium falciparum strains to seven endoperoxide antimalarial drugs. The susceptibility of all of the DCP lines to six of the drugs was lower than that of the controls. In contrast, DCP parasites did not show reduced susceptibility to the synthetic endoperoxide drug OZ439. These data show that it is possible to circumvent emerging artemisinin resistance with a modified endoperoxide drug.

Topics: Adamantane; Antimalarials; Artemether; Artemisinins; Dose-Response Relationship, Drug; Drug Resistance; Heterocyclic Compounds, 1-Ring; Inactivation, Metabolic; Lethal Dose 50; Microbial Sensitivity Tests; Peroxides; Plasmodium falciparum; Spiro Compounds

Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca²⁺-ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane) was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy.. Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay.. The sum 50% and 90% fractional inhibitory concentration (∑FIC₅₀, ₉₀) of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4.. The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.

Topics: Antimalarials; Artemisinins; Drug Interactions; Heterocyclic Compounds, 1-Ring; Hypoxanthine; Isotope Labeling; Peroxides; Plasmodium falciparum; Spiro Compounds; Thapsigargin; Tritium

A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.

Topics: Administration, Oral; Animals; Antimalarials; Antineoplastic Agents; Artemisinins; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Stability; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Mice; Sulfones

Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.

Topics: Antimalarials; Artemisinins; Drug Stability; Hemoglobins; Humans; Molecular Structure; Peroxides; Spectrophotometry

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

Topics: Alkylation; Animals; Antimalarials; Artemisinins; Heme; Humans; Kinetics; Parasitic Sensitivity Tests; Plasmodium falciparum; Spiro Compounds; Structure-Activity Relationship

RBX11160 (OZ277) is a fully synthetic peroxidic antimalarial in clinical development. To study the possible mechanisms of action of RBX11160, we have examined its ability to inhibit PfATP6, a sarcoplasmic reticulum calcium ATPase and proposed target for semisynthetic peroxidic artemisinin derivatives. RBX11160 inhibits PfATP6 (apparent half-maximal inhibitory constant=7,700 nM) less potently than artemisinin (79 nM). Inhibition of PfATP6 is abrogated by desferrioxamine, an iron-chelating agent. Consistent with this finding, the killing of Plasmodium falciparum organisms by RBX11160 in vitro is antagonized by desferrioxamine. Artesunate and RBX11160 also act antagonistically against P. falciparum in vitro. A fluorescent derivative of RBX11160 localizes to the parasite cytosol in some parasites and to the food vacuole in other parasites. These data demonstrate that there are both similarities and differences between the antimalarial properties of RBX11160 and those of semisynthetic antimalarials such as artesunate and artemisinin.

Topics: Animals; Antimalarials; Artemisinins; Artesunate; Calcium-Transporting ATPases; Heterocyclic Compounds, 1-Ring; Malaria, Falciparum; Microscopy, Confocal; Peroxides; Plasmodium falciparum; Sesquiterpenes; Spiro Compounds

Topics: Animals; Antimalarials; Artemisinins; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Peroxides; Sesquiterpenes; Spiro Compounds

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.

Topics: Animals; Antimalarials; Artemisinins; Biological Availability; Drug Design; Drug Evaluation, Preclinical; Half-Life; Heterocyclic Compounds, 1-Ring; Humans; Inhibitory Concentration 50; Malaria; Mice; Oxidation-Reduction; Peroxides; Plasmodium berghei; Plasmodium falciparum; Rats; Rats, Wistar; Sesquiterpenes; Solubility; Spiro Compounds; Tissue Distribution

Topics: Antimalarials; Artemisinins; Clinical Trials as Topic; Drug Costs; Drug Design; Drug Therapy, Combination; Heterocyclic Compounds, 1-Ring; Humans; Malaria; Peroxides; Research Support as Topic; Sesquiterpenes; Spiro Compounds; Thailand