Synthesis of Tetrasubstituted Ozonides by the Griesbaum Coozonolysis Reaction:  Diastereoselectivity and Functional Group Transformations by Post-Ozonolysis Reactions

Tang, Yang; Dong, Yuxiang; Karle, Jean M.; DiTusa, Charles A.; Vennerstrom, Jonathan L.

doi:10.1021/jo040171c

Cited by 81 publications

(80 citation statements)

References 25 publications

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“…The trioxolanes were synthesized via Griesbaum coozonolysis and post-ozonolysis modifications as previously described (6,7,26,(30)(31)(32)(33). Artemisinin (98%), dihydroartemisinin (97%), hemin (Ն80%) and sodium hydrosulfite (sodium dithionite) (ϳ85%) were obtained from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

Creek

Charman

Chiu

et al. 2008

Antimicrob Agents Chemother

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103

111

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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 (R 2 ‫؍‬ 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.

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Section: Methodsmentioning

confidence: 99%

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

Creek

Charman

Chiu

et al. 2008

Antimicrob Agents Chemother

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103

111

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“…1,2,4-Trioxolanes OZ01, OZ03, OZ78, OZ209, and OZ288, 1,2,4-trioxanes ST01 and ST03, and 1,3-dioxolanes NP17 and NP18 (Fig. 1) were synthesized as previously described (4,20,21,27). The compounds were prepared as suspensions in 7% (vol/vol) Tween 80 and 3% (vol/vol) ethanol before oral administration.…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

Xiao

Keiser

Chollet

et al. 2007

Antimicrob Agents Chemother

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176

138

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Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 g/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

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“…[215] If the outcome of phase II studies confirm the promising preclinical results, OZ-277 could become an easily accessible alternative to artesunate (42) owing to its short and straightforward synthesis. [216] Development of a pediatric formulation and an intravenous formulation is in progress. Piperaquine (27) has been selected as a first combination partner.…”

Section: Oz-277mentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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Synthesis of Tetrasubstituted Ozonides by the Griesbaum Coozonolysis Reaction: Diastereoselectivity and Functional Group Transformations by Post-Ozonolysis Reactions

Cited by 81 publications

References 25 publications

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

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