1,2,4-Trioxanes as potential antimalarial agents

Kepler, John A.; Philip, A.; Lee, YW; Morey, Matthew C.; Carroll, F. Ivy

doi:10.1021/jm00399a004

Cited by 64 publications

(16 citation statements)

References 4 publications

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“…1 Generally, singlet oxygen is the reagent of choice in these processes, requiring the use of an external sensitizer for the energy transfer process to occur. [2][3][4][5] During our studies on the photochemical behavior of dienones in the presence of molecular oxygen, we established an easy one-pot approach for the preparation of bridged 1,2,4-trioxanes (Scheme 1). [6][7][8] The process involves a singlet 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 oxygen Diels-Alder type oxygenation of 2H-pyran in situ generated intermediates, revealing the ability of dienones bearing an ionone-type skeleton to act as singlet oxygen sensitizers.…”

Section: Introductionmentioning

confidence: 99%

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings

et al. 2015

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The UVA (350 nm) irradiation of an α-pyran in the presence of oxygen led to the unexpected formation of a tetraoxygenated compound whose structure could not be unambiguously determined on the basis of conventional (1)H-(13)C correlated experiments. 1,1-ADEQUATE (adequate double quantum transfer experiment) and 1,n-ADEQUATE combined with computer-assisted structure elucidation software led to two structural possibilities involving the formation of either an epoxide or an oxetane. Residual dipolar couplings allowed not only the identification of the compound as a spiroepoxide but also the determination of its relative configuration. To account for its formation, we propose a bisepoxide intermediate that, as opposed to most α,β-epoxyketones under irradiation, undergoes O-Cβ cleavage probably due to the presence of an extra oxygen substituent in the β position. 1,2-Acyl migration would then proceed stereoselectively to the final product obtained as a single diastereomer.

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Section: Introductionmentioning

confidence: 99%

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings

et al. 2015

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“…However, 38b was inactive in the Rane test. 42,90 Trioxane 39 and its 3-hydroxymethyl and 3-hydroxyhexyl analogs were prepared by treating 1,4-dihydro-1,4-dimethyl-1,4-epidioxynaphthalene with the corresponding aldehydes in the presence of acid. The trioxolane alcohols were also converted into five carbamate and ester derivatives.…”

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confidence: 99%

Synthetic peroxides as antimalarials

Tang

Dong²,

Vennerstrom³

2004

Medicinal Research Reviews

265

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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“…Introduction. -Ever since the discovery that arteannuin (1) is a potent antimalarial agent [ 1-31, there has been a growing interest in the synthesis, chemistry, and physical properties of the intrinsic structural feature of this unique natural product, namely the 1,2,4-trioxane ring and its congeners [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. From a study of the vibrational spectra of 1 and its lactol derivatives, it has been concluded [18] that the peroxide linkage contained therein is characterized by a frequency at 722 cm-'.…”

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confidence: 99%