Synthesis and Antimalarial Activity of Sixteen Dispiro-1,2,4,5-tetraoxanes: Alkyl-Substituted 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes

Authors

Jonathan L. Vennerstrom, University of Nebraska Medical CenterFollow
Yuxiang Dong, University of Nebraska Medical CenterFollow
Walter Reed Army Institute of Research
Arba L. Ager Jr., University of Miami
Hong-Ning Fu, University of Nebraska Medical Center
Walter Reed Army Institute of Research
Walter Reed Army Institute of Research
Walter Reed Army Institute of Research
Walter Reed Army Institute of Research
sheri M. Walters, University of Nebraska at Omaha
James K. Wood, The University of Nebraska at OmahaFollow
Geoffrey Edwards, University of Liverpool
Alexandra D. Holme, University of Liverpool
W. Graham McLean, University of Liverpool
Walter Reed Army Institute of Research

Document Type

Article

Publication Date

7-2000

Publication Title

Journal of Medicinal Chemistry

Volume

43

Issue

14

First Page

2753

Last Page

2758

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 H₂-SO₄/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.

Comments

Copyright © 2000 American Chemical Society.

Recommended Citation

Vennerstrom, Jonathan L.; Dong, Yuxiang; Walter Reed Army Institute of Research; Ager, Arba L. Jr.; Fu, Hong-Ning; Walter Reed Army Institute of Research; Walter Reed Army Institute of Research; Walter Reed Army Institute of Research; Walter Reed Army Institute of Research; Walters, sheri M.; Wood, James K.; Edwards, Geoffrey; Holme, Alexandra D.; McLean, W. Graham; and Walter Reed Army Institute of Research, "Synthesis and Antimalarial Activity of Sixteen Dispiro-1,2,4,5-tetraoxanes: Alkyl-Substituted 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes" (2000). Chemistry Faculty Publications. 16.
https://digitalcommons.unomaha.edu/chemfacpub/16