Antimalarially potent, easily prepared, fluorinated endoperoxides

Posner, Gary H.; Tao, Xiaowan; Cumming, Jared N.; Klinedinst, Donna; Shapiro, Theresa A.

doi:10.1016/0040-4039(96)01625-5

Cited by 37 publications

(29 citation statements)

References 21 publications

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“…The stereochemistry of compounds 3a and 4a was then conclusively assigned through two-dimensional 2D ROESY (rotational nuclear Overhauser effect spectroscopy) NMR of the ring-opened derivative of compound 3a, confirming that it had the stereochemistry tentatively assigned by Turner and Herz (67). Endoperoxide 2b was synthesized as outlined by Posner et al (54), with epoxidation performed as was done with the ascaridole derivatives (Fig. 1, scheme 1) and stereochemical determination through two-dimensional ROESY NMR of the epoxides.…”

Section: Resultsmentioning

confidence: 80%

“…Building on our previous research into epoxyendoperoxides as antimalarial drug candidates (64), we have examined the epoxides of bicyclic endoperoxides 2a to 2d, which contain tetrasubstituted carbons adjacent to the peroxide linkage. Endoperoxides 2a and 2c have previously been assessed as antimalarials against the NF54 strain of P. falciparum (54). Epoxidation of these endoperoxides gave two isomers with the epoxide trans (compound 3) and cis (compound 4) to the peroxide linkage (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Diene 1b was synthesized by the general procedure outlined by Posner et al (54) 1-Bromo-4-fluorobenzene. To a two-necked round-bottom flask equipped with a condenser and a dropping funnel were added fluorobenzene (5 g; 52 mmol) and FeCl 3 (100 mg).…”

Section: Methodsmentioning

confidence: 99%

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Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Crespo¹,

Avery

Hanssen

et al. 2008

Antimicrob Agents Chemother

113

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Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.Artemisinin is a sesquiterpene lactone antimalarial with a 1,2,4-trioxane heterocyclic core that incorporates a peroxide linkage that is essential for its activity (44). Artemisinin is of major importance as a frontline treatment for malaria, particularly as it is active against chloroquine (CQ)-resistant strains of Plasmodium falciparum (20,23,24,45,66,74). Several groups have reported on pathways for the synthesis of artemisinin, but all require numerous steps and have low yields (5, 35). As a result, artemisinin-based antimalarials are produced semisynthetically from extracts of Artemisia annua. A period of over 1 year is needed for the horticultural, harvesting, extraction, and manufacturing processes (34,41,45), which limits the ease of scale-up of production and makes artemisinin derivatives much more expensive than traditional antimalarials, such as CQ and sulfadoxine-pyrimethamine. Indeed, artemisinin combinations are too costly for many patients, and the supply of counterfeit or inferior drugs is a major problem (4, 45, 71). Another issue is the fact that artemisinin and its derivatives are not suitable for prophylaxis or for use as a monotherapy due to their very short half-lives in vivo. T...

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Crespo¹,

Avery

Hanssen

et al. 2008

Antimicrob Agents Chemother

113

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“…9 However, the assay may underestimate the potency of these volatile compounds. In addition, the highly lipophilic character of 4 and 5 might be a drawback for an enhanced antimalarial activity.…”

Section: Nhrmentioning

confidence: 99%

“…The observation that saturated bicyclic endoperoxides are more potent antimalarials relative to their unsaturated counterparts, 9 urged us to reduce the endoperoxides 29-32 with in situ generated diimide (HN=NH). 18 The reaction was very clean without affecting the peroxide O-O bond, and the novel saturated endoperoxides 38-41 were isolated in almost quantitative yield.…”

Section: Dihydroascararidole Derivativesmentioning

confidence: 99%

Synthesis of novel polar derivatives of the antimalarial endoperoxides ascaridole and dihydroascaridole

Hatzakis¹,

Opsenica²,

Šolaja³

et al. 2006

Arkivoc

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Dedicated to Professor Waldemar Adam on the occasion of his 70th birthdate, and for his remarkable contribution in the chemistry of peroxides AbstractNovel polar derivatives of the antimalarial endoperoxide ascaridole were synthesized based on the zeolite NaY-promoted isomerization of perillyl and nopol derivatives to conjugated cyclohexadienes, followed by reaction with singlet oxygen. Several unsaturated endoperoxides were in situ reduced with diimide to form dihydroascaridole derivatives, as well.

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Antimalarial Agents

Casteel¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Malaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome of Plasmodium falciparum . New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy. “If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases 1 .” “Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”

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Antimalarially potent, easily prepared, fluorinated endoperoxides

Cited by 37 publications

References 21 publications

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Synthesis of novel polar derivatives of the antimalarial endoperoxides ascaridole and dihydroascaridole

Antimalarial Agents

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