Antimalarial Trioxanes Research Articles

Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine.

The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99–411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99–411 and of piperaquine and 99–411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99–411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99–411 significantly decreased the systemic exposure of piperaquine by half-fold while it had no effect on the kinetics of lumefantrine. 99–411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99–411, an in situ permeability study was performed by co-perfusing lumefantrine and 99–411. In presence of lumefantrine, the absorption of 99–411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99–411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99–411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well.

Conversion of Dihydroartemisinic Acid into Dihydro‐epi‐deoxyarteannuin B

AbstractA facile and high‐yielding one‐step conversion of dihydroartemisinic acid into dihydro‐epi‐deoxyarteannuin B, a natural product and a pivotal compound in the synthesis of several other natural products isolated from Artemisia annua L., was developed after the systematic examination of several potentially applicable conditions. The transformation, most satisfactorily effected with Pd(OAc)2/CuCl2/MnO2, makes it possible to access many known potent antimalarial trioxanes from readily available artemisinic acid. Some interesting cases of differentiation between the carbonyl groups are also presented.

Diversification in the synthesis of antimalarial trioxane and tetraoxane analogs

Artemisinin and its semi synthetic analogs have established themselves as effective antimalarial drugs. Since artemisinin is naturally isolated, in short supply and is very expensive to synthesize, extensive research on the discovery of peroxidic antimalarial compounds has intrigued scientists to explore structurally simple yet diverse cyclic peroxides. Consequently, trioxanes and tetraoxanes have been identified as promising candidates for the development of the next generation of antimalarial drugs. To combine the latest synthetic routes and methodologies employed in their synthesis along with earlier reports (dating back to 1899), we present an integrated overview on the diversified synthesis of trioxanes, tetraoxanes and their hybrids.

ChemInform Abstract: Synthesis of Antimalarial Trioxanes via Continuous Photo‐Oxidation with 1O2 in Supercritical CO2.

AbstractThe continuous photo‐oxidation of allylic alcohol (I) to its hydroperoxides (II) as a key step of the synthesis of antimalarial trioxanes such as (IV) is described.

Synthesis of antimalarialtrioxanesvia continuous photo-oxidation with1O2in supercritical CO2

The oxidation of an allylic alcohol to its hydroperoxides represents a key step in the synthesis of a series of spirobicyclic, antimalarial trioxanes. Herein, we investigate the continuous photo-oxidation of an allylic alcohol with 1O2 in scCO2, as a ‘green’ alternative to conventional methods, and examine the remaining two steps in the synthesis of antimalarial trioxanes from readily available starting materials.

ChemInform Abstract: Access to Some UV Chromophore‐Containing Antimalarial Trioxanes Using Hydrogen Peroxide as Source of the Peroxy Bonds.

AbstractThe readily accessible UV‐chromophore (II), containing an epoxide moiety, enables access to a range of trioxanes by perhydrolysis and ketalization.

Access to Some UV Chromophore-Containing Antimalarial Trioxanes Using Hydrogen Peroxide as Source of the Peroxy Bonds

Several trioxanes were synthesized through perhydrolysis of an allylic epoxide followed by ketal exchange with a proper dimethyl ketal.

ChemInform Abstract: Alkylating Properties of Synthetic Trioxanes Related to Artemisinin.

The synthesis and reactivity toward a haem model of trioxane derivatives bearing a 1,2-dioxacyclohexane cycle instead of a 1,2-dioxacycloheptane as in artemisinin, and lacking the lactone ring, are reported. The fact that a trioxane able to generate a C-centred radical (without alkylating ability toward a haem model) was devoid of toxicity against Plasmodium also suggests that the efficiency of antimalarial trioxanes is not due to an oxidant stress.

Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid bodies of trophozoites and schizonts, and surrounding the developing merozoite membranes. Artemisinin pre-treatment significantly reduced fluorescent labeling of neutral lipid bodies, while iron chelation increased non-specific cytoplasmic localization. To further explore the effects of endoperoxides on cellular lipids, we used an oxidation-sensitive BODIPY lipid probe to show the presence of artemisinin-induced peroxyl radicals in parasite membranes. Lipid extracts from artemisinin-exposed parasites contained increased amounts of free fatty acids and a novel cholesteryl ester . The cellular accumulation patterns and effects on lipids were entirely endoperoxide-dependent, as inactive dioxolane analogs lacking the endoperoxide moiety failed to label neutral lipid bodies or induce oxidative membrane damage. In the parasite digestive vacuole, neutral lipids closely associate with heme and promote hemozoin formation. We propose that the trioxane artemisinin and its derivatives are activated by heme-iron within the neutral lipid environment where they initiate oxidation reactions that damage parasite membranes.

Heme Alkylation by Artesunic Acid and Trioxaquine DU1301, Two Antimalarial Trioxanes

The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug-resistant Plasmodium falciparum strains, contains a 1,2,4-trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs. The reductive activation of the peroxide function of artemisinin by iron(II)-heme produces heme derivatives that are alkylated at meso positions by a C-centered radical derived from artemisinin. We checked if the alkylating ability of trioxane-based drugs toward heme, which might be related to its parasiticidal activity, is a general feature by comparing the chemical reactivity toward heme of the clinically relevant derivative artesunic acid and DU1301, a drug of the trioxaquine family, that is active against P. falciparum. Both artesunic acid and trioxaquine DU1301 efficiently alkylated the heme macrocycle after activation of their peroxide function by the iron(II) of heme itself and thus gave rise to covalently coupled heme-drug products. This heme-drug adduct formation might be related to the high antimalarial activity of DU1301.

Structure-activity relationship study of steroidal 1,2,4,5-tetraoxane animalarials using computational procedures

A three-dimensional QSAR pharmacophore model for antimalarial activity of steroidal 1,2,4,5-tetraoxanes was developed from a set of 17 substituted antimalarial derivatives out of 27 analogues that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and one hydrophobic (aliphatic) feature, was found to map well onto the potent analogues and many other well-known antimalarial trioxane drugs including artemisinin, arteether, artesunic acid, and tetraoxanes. The presence of at least one hydrogen bond acceptor in the trioxane or the tetraoxane moiety appears to be necessary for potent activity of this class of compounds. Docking calculations of some of these compounds with heme are consistent with the above observation as the proximity of the heme iron to the oxygen atom of the trioxane or the tetraoxane moiety favors potent activity of the compounds. Electron transfer from the oxygen of trioxane or the tetraoxane appears to be crucial for mechanism of action of the compounds. This information together with the pharmacophore should enable search for new peroxide containing antimalarial candidates from databases and custom designed synthesis of more efficacious and safer analogues.

Knowledge of the Proposed Chemical Mechanism of Action and Cytochrome P450 Metabolism of Antimalarial Trioxanes Like Artemisinin Allows Rational Design of New Antimalarial Peroxides

AbstractFor Abstract see ChemInform Abstract in Full Text.

Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides.

Evidence is reviewed elucidating the mechanism of iron-induced triggering of antimalarial trioxanes. As prodrugs, trioxanes undergo homolytic, inner-sphere, reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon radicals, high-valent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds. One or more of these reactive intermediates and neutral alkylating agents likely kill the malaria parasites. Several new, orally active antimalarial peroxides have been designed rationally based on this fundamental mechanistic paradigm. Incorporating metabolism-blocking substituents also provides some new, potent, semi-synthetic artemisinin derivatives.

A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides.

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of beta-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

Antimalarial Chemotherapy. Mechanisms of Action, Resistance and New Directions in Drug Discovery

I. Introduction The Need for New Approaches to Antimalarial Chemotherapy Philip J. Rosenthal and Louis H. Miller The History of Antimalarial Drugs Steven R. Meshnick and Mary J. Dobson Transport and Trafficking in Plasmodium-Infected Red Cells Kasturi Haldar and Thomas Akompong The Plasmodium Food Vacuole Ritu Banerjee and Daniel E. Goldberg Clinical and Public Health Implications of Antimalarial Drug Resistance Piero L. Olliaro and Peter B. Bloland II. Established Antimalarial Drugs and Compounds Under Clinical Development Chloroquine and Other Quinoline Antimalarials Leann Tilley, Paul Loria, and Mick Foley 8-Aminoquinolines Ralf P. Brueckner, Colin Ohrt, J. Kevin Baird, and Wilbur K. Milhous Mechanisms of Quinoline Resistance Grant Dorsey, David A. Fidock, Thomas E. Wellems, and Philip J. Rosenthal Folate Antagonists and Mechanisms of Resistance Christopher V. Plowe Artemisinin and Its Derivatives Steven R. Meshnick. Atovaquone-Proguanil Combination, Akhil B. Vaidya The Antimalarial Drug Portfolio and Research Pipeline Piero L. Olliaro and Wilbur K. Milhous III. New Compounds, New Approaches, and New Targets Novel Quinoline Antimalarials Paul A. Stocks, Kaylene J. Raynes, and Stephen A. Ward New Antimalarial Trioxanes and Endoperoxides Gary H. Posner, Mikhail Krasavin, Michael McCutchen, Poonsakdi Ploypradith, John P. Maxwell, Jeffrey S. Elias, and Michael H. Parker Antibiotics and the Plasmodial Plastid Organelle Barbara Clough and R. J. M. (Iain) Wilson Fresh Paradigms for Curative Antimetabolites Pradipsinh K. Rathod. Iron Chelators, Mark Loyevsky and Victor R. Gordeuk Protease Inhibitors Philip J. Rosenthal Inhibitors of Phospholipid Metabolism Henri Joseph Vial and Michele Calas Development of New Malaria Chemotherapy by Utilization of Parasite-Induced Transport Annette M. Gero and Alexander L. Weis

Alkylation of manganese(II) tetraphenylporphyrin by a synthetic antimalarial trioxane.

The synthesis and the antimalarial activity of a new kind of polycyclic 1,2,4-trioxanes are reported. The alkylation of the heme model MnIITPP by the biologically active (IC 50 = 320 nmol L-1) hemiperketal 2 is presented.

Orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents.

Short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. Almost exclusive formation of the trioxane 12alpha-stereoisomers simplifies product purification. Carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 degrees C for 24 h. When administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. Important for their practical in vivo administration, these new synthetic antimalarial trioxanes 3 and 5 are 14-20 times more soluble in water at pH 7.4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate.

Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model.

The reactivity of 1,2,4-trioxane molecules 2-5, structurally related to the antimalarial drug artemisinin, with a heme model, manganese(II) tetraphenylporphyrin, is reported. With the pharmacologically active drugs 2-4, covalent adducts were obtained by addition of a drug-derived radical onto the porphyrin macrocycle, whereas no reaction was obtained with the nonactive compound 5. This confirms that alkylation is probably one of the key factors of the pharmacological activity of endoperoxide-based antimalarial drugs.

Alkylating properties of synthetic trioxanes related to artemisinin

The synthesis and reactivity toward a haem model of trioxane derivatives bearing a 1,2-dioxacyclohexane cycle instead of a 1,2-dioxacycloheptane as in artemisinin, and lacking the lactone ring, are reported. The fact that a trioxane able to generate a C-centred radical (without alkylating ability toward a haem model) was devoid of toxicity against Plasmodium also suggests that the efficiency of antimalarial trioxanes is not due to an oxidant stress.

ChemInform Abstract: Orally Active, Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin Family.

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