Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes

Alkyl-substituted 7,8,15,16- tetraoxadispiro[5.2.5.2]hexadecanes

Jonathan L Vennerstrom, Yuxiang Dong, Steven L. Andersen, Arba L. Ager, Hong Ning Fu, Robert E. Miller, David L. Wesche, Dennis E. Kyle, Lucia Gerena, Sheri M. Walters, James K. Wood, Geoffrey Edwards, Alexandra D. Holme, W. Graham McLean, Wilbur K. Milhous

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Abstract

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50's > 1000 nM), but five (2, 6, 10, 11, 12) had IC50's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC50's of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei- infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

Original languageEnglish (US)
Pages (from-to)2753-2758
Number of pages6
JournalJournal of Medicinal Chemistry
Volume43
Issue number14
DOIs
StatePublished - Jul 13 2000

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Tetraoxanes
Antimalarials
Inhibitory Concentration 50
Chloroquine
n-hexadecane
Animals

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes : Alkyl-substituted 7,8,15,16- tetraoxadispiro[5.2.5.2]hexadecanes. / Vennerstrom, Jonathan L; Dong, Yuxiang; Andersen, Steven L.; Ager, Arba L.; Fu, Hong Ning; Miller, Robert E.; Wesche, David L.; Kyle, Dennis E.; Gerena, Lucia; Walters, Sheri M.; Wood, James K.; Edwards, Geoffrey; Holme, Alexandra D.; McLean, W. Graham; Milhous, Wilbur K.

In: Journal of Medicinal Chemistry, Vol. 43, No. 14, 13.07.2000, p. 2753-2758.

Research output: Contribution to journalArticle

Vennerstrom, JL, Dong, Y, Andersen, SL, Ager, AL, Fu, HN, Miller, RE, Wesche, DL, Kyle, DE, Gerena, L, Walters, SM, Wood, JK, Edwards, G, Holme, AD, McLean, WG & Milhous, WK 2000, 'Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes: Alkyl-substituted 7,8,15,16- tetraoxadispiro[5.2.5.2]hexadecanes', Journal of Medicinal Chemistry, vol. 43, no. 14, pp. 2753-2758. https://doi.org/10.1021/jm0000766
Vennerstrom, Jonathan L ; Dong, Yuxiang ; Andersen, Steven L. ; Ager, Arba L. ; Fu, Hong Ning ; Miller, Robert E. ; Wesche, David L. ; Kyle, Dennis E. ; Gerena, Lucia ; Walters, Sheri M. ; Wood, James K. ; Edwards, Geoffrey ; Holme, Alexandra D. ; McLean, W. Graham ; Milhous, Wilbur K. / Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes : Alkyl-substituted 7,8,15,16- tetraoxadispiro[5.2.5.2]hexadecanes. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 14. pp. 2753-2758.
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abstract = "Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50's > 1000 nM), but five (2, 6, 10, 11, 12) had IC50's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC50's of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei- infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40{\%} and 60{\%} of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100{\%} of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.",
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T1 - Synthesis and antimalarial activity of sixteen dispiro- 1,2,4,5-tetraoxanes

T2 - Alkyl-substituted 7,8,15,16- tetraoxadispiro[5.2.5.2]hexadecanes

AU - Vennerstrom, Jonathan L

AU - Dong, Yuxiang

AU - Andersen, Steven L.

AU - Ager, Arba L.

AU - Fu, Hong Ning

AU - Miller, Robert E.

AU - Wesche, David L.

AU - Kyle, Dennis E.

AU - Gerena, Lucia

AU - Walters, Sheri M.

AU - Wood, James K.

AU - Edwards, Geoffrey

AU - Holme, Alexandra D.

AU - McLean, W. Graham

AU - Milhous, Wilbur K.

PY - 2000/7/13

Y1 - 2000/7/13

N2 - Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50's > 1000 nM), but five (2, 6, 10, 11, 12) had IC50's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC50's of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei- infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

AB - Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50's > 1000 nM), but five (2, 6, 10, 11, 12) had IC50's between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC50's of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei- infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

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