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

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 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 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 beta-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 beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

• Authors: Mario D Bachi, Edward E Korshin, Roland Hoos, Alex M Szpilman, Poonsakdi Ploypradith, Suji Xie, Theresa A Shapiro, Gary H Posner
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 12 Pg. 2516-33 (Jun 05 2003) ISSN: 0022-2623 [Print] United States
• PMID: 12773055 (Publication Type: Journal Article)

Chemical References

• 8-acetoxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo(3.3.1)nonane
• 8-benzyloxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo(3.3.1)nonane
• Antimalarials
• Bridged Bicyclo Compounds, Heterocyclic
• Sulfones

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Malaria (drug therapy, parasitology)
• Male
• Mice
• Mice, Inbred ICR
• Plasmodium berghei
• Plasmodium falciparum (drug effects)
• Stereoisomerism
• Structure-Activity Relationship
• Sulfones (chemical synthesis, chemistry, pharmacology)