Synthesis and Antimalarial Activity of 11 Dispiro-1,2,4,5-tetraoxane Analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes Substituted at the 1 and 10 Positions with Unsaturated and Polar Functional Groups

Authors

Yuxiang Dong, University of Nebraska Medical CenterFollow
F. Hoffmann-LaRoche Ltd.
Jacques Chollet, Swiss Tropical Institute, Basel
Ronald Kaminsky, Swiss Tropical Institute, Basel
James K. Wood, The University of Nebraska at OmahaFollow
Jonathan L. Vennerstrom, University of Nebraska Medical CenterFollow

Document Type

Article

Publication Date

4-1999

Publication Title

Journal of Medicinal Chemistry

Volume

42

Issue

8

First Page

1477

Last Page

1480

Abstract

Eleven novel dispiro-1,2,4,5-tetraoxanes 3 bearing unsaturated and polar functional groups were designed to enhance the oral antimalarial activity of the prototype tetraoxane 2 (WR 148999). With the exception of 3g and 3h, tetraoxanes 3 were available via the peroxidation of corresponding cyclohexanone derivatives in H2SO4/CH3CN. Tetraoxanes 3g and 3h were prepared by hydrolysis of ester tetraoxanes 3e and 3i, respectively. Five of the 11 tetraoxanes were inactive, but six tetraoxanes had IC₅₀ values of 6-26 nM against the K1 and NF54 strains of Plasmodium falciparum compared to corresponding IC₅₀ values of 28 and 39 nM for 2, and 10 and 12 nM for artemisinin (1). Ester tetraoxane 3e was the most active in vitro, some 2-fold more potent than 1. However, none of the six tetraoxanes active in vitro were as effective as either 1 or 2 in vivo; at single doses of 100 mg/kg most possessed little to no vivo activity in mice infected with Plasmodium berghei. Unsaturated tetraoxane 3a was uniquely more active when administered per os (po) than subcutan (sc). For this series of tetraoxanes, the discrepancy between vitro and vivo activities underscores the limitations of conclusions drawn solely from in vitro antimalarial data and illustrates a practical benefit of complementary single-dose in vivo antimalarial screens.

Comments

Copyright © 1999 American Chemical Society.

Recommended Citation

Dong, Yuxiang; F. Hoffmann-LaRoche Ltd.; Chollet, Jacques; Kaminsky, Ronald; Wood, James K.; and Vennerstrom, Jonathan L., "Synthesis and Antimalarial Activity of 11 Dispiro-1,2,4,5-tetraoxane Analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes Substituted at the 1 and 10 Positions with Unsaturated and Polar Functional Groups" (1999). Chemistry Faculty Publications. 18.
https://digitalcommons.unomaha.edu/chemfacpub/18