arteflene and Malaria

The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented.

Topics: Aminoquinolines; Animals; Antimalarials; Drug Delivery Systems; Drug Discovery; Drug Resistance; Humans; Malaria; Molecular Targeted Therapy; Peroxides; Plasmodium; Polypharmacology

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.

Topics: Animals; Antimalarials; Bridged Bicyclo Compounds, Heterocyclic; Malaria; Male; Mice; Mice, Inbred ICR; Plasmodium berghei; Plasmodium falciparum; Stereoisomerism; Structure-Activity Relationship; Sulfones

The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Bridged Bicyclo Compounds, Heterocyclic; Chemistry, Pharmaceutical; Corn Oil; Drug Carriers; Drug Evaluation, Preclinical; Injections, Subcutaneous; Lipids; Malaria; Mice; Parasitemia; Peroxides; Plasmodium berghei; Plasmodium yoelii; Sesquiterpenes; Spiro Compounds; Styrenes; Water

The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antimalarials; Artemisinins; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Female; In Vitro Techniques; Malaria; Male; Mice; Mutagenicity Tests; Peroxides; Plasmodium berghei; Pregnancy; Rabbits; Rats; Reproduction; Styrenes; Time Factors

The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.

Topics: Animals; Antimalarials; Artemisinins; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Drug Interactions; Humans; In Vitro Techniques; Malaria; Male; Mice; Peroxides; Plasmodium berghei; Plasmodium falciparum; Styrenes