A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic β-sulfonyl-endoperoxides

Mario D. Bachi, Edward E. Korshin, Roland Hoos, Alex M. Szpilman, Poonsakdi Ploypradith, Suji Xie, Theresa A. Shapiro, Gary H. Posner

Research output: Contribution to journalArticle

Abstract

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R1 = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). β-Sulfenyl peroxides 9 and 10 (R1 = OH) are converted into β-sulfinyl and β-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the terthydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure β-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC50 = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of β-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of β-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

Original languageEnglish (US)
Pages (from-to)2516-2533
Number of pages18
JournalJournal of medicinal chemistry
Volume46
Issue number12
DOIs
StatePublished - Jun 5 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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