title: 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.affiliation: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel. mario.bachi@weizmann.ac.il
authors.forename: Mario D
authors.initials: MD
authors.lastname: Bachi
authors.forename: Edward E
authors.initials: EE
authors.lastname: Korshin
authors.forename: Roland
authors.initials: R
authors.lastname: Hoos
authors.forename: Alex M
authors.initials: AM
authors.lastname: Szpilman
authors.forename: Poonsakdi
authors.initials: P
authors.lastname: Ploypradith
authors.forename: Suji
authors.initials: S
authors.lastname: Xie
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Shapiro
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C475433:8-acetoxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo(3.3.1)nonane; C475434:8-benzyloxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo(3.3.1)nonane; D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013450:Sulfones