A carbonyl oxide route to antimalarial yingzhaosu A analogues: Synthesis and antimalarial activity

Neill, Paul M. O'; Searle, Natalie L.; Raynes, Kaylene J.; Maggs, James L.; Ward, Stephen A.; Storr, R. C.; Park, B.Kevin; Posner, Gary H.

doi:10.1016/s0040-4039(98)01248-9

Cited by 62 publications

(22 citation statements)

References 8 publications

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“…Artemisinin and other related trioxane-based antimalarials exerts antimalarial activity due to their ability to interact with ferriprotoporphyrin IX (heme) in the acidic food vacuole of the parasite, which results in the generation of cytotoxic carbon-centered radical. On the basis of this knowledge several approaches have been investigated that includes the incorporation of groups to enhance the stability of the proposed intermediate [61][62][63][64] and covalent attachment of iron chilator functionality 65 or aminoquinolines to enhance the interaction of the peroxide bridge with available free iron in the acidic food vacuole of the parasite.…”

Section: Tetraoxane-amine and Aminoquinoline Conjugatesmentioning

confidence: 99%

Tetraoxanes: Synthetic and Medicinal Chemistry Perspective

Kumar¹,

Savan²,

Rawat

2010

Medicinal Research Reviews

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The discovery of artemisinin from Chinese medicinal plant, Artemisia annua in 1971, opened a new era in the malarial chemotherapy. This discovery was the beginning of exploring peroxides as potential replacements for the traditional antimalarial drugs such as chloroquine and mefloquine. The structurally simple class of peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. This study describes the current status of tetraoxane-based antimalarials that show significant promises because of their artemisinin-like activity. Literature from 1999 has been critically reviewed and an attempt has been made to discuss various synthetic methods and structure-activity relationship study among the series of tetraoxane-based compounds. © 2010 Wiley Periodicals, Inc. Med Res Rev.

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Section: Tetraoxane-amine and Aminoquinoline Conjugatesmentioning

confidence: 99%

Tetraoxanes: Synthetic and Medicinal Chemistry Perspective

Kumar¹,

Savan²,

Rawat

2010

Medicinal Research Reviews

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“…46 Of these, 15 was the best, only 8-fold less potent than 1. Figure 6: Based on the framework of 3, O'Neill et al 49 reported an efficient synthesis of endoperoxide ketals. Ozonolysis of (R)-carvone and in situ trapping of the carbonyl oxide with primary alcohols produced a 1:1 mixture of diastereomeric hydroperoxy ketals that were cyclized by a subsequent intramolecular conjugate addition to form five target endoperoxide ketals.…”

Section: U N S a T U R A T E D 1 2 -D I O X A N E S ( E N D O P Ementioning

confidence: 99%

Synthetic peroxides as antimalarials

Tang

Dong²,

Vennerstrom³

2004

Medicinal Research Reviews

260

123

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The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

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“…Posner and co-workers have described the intramolecular attack of a tertiary hydroperoxide group on the α,β-unsaturated carbonyl of carvone. [11] In this case, the spatial proximity of the two groups favoured the reaction. Finally, Woerpel and co-workers have recently synthesised 1,2-dioxane systems by intramolecular palladium-catalysed addition of hydroperoxides to olefins.…”

Section: Introductionmentioning

confidence: 93%