Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols

被引：15

作者：

Amewu, Richard ^{[1
]}

Gibbons, Peter ^{[1
]}

Mukhtar, Amira ^{[1
]}

Stachulski, Andrew V. ^{[1
]}

Ward, Stephen A. ^{[2
]}

Hall, Charlotte ^{[2
]}

Rimmer, Karen ^{[2
]}

Davies, Jill ^{[2
]}

Vivas, Livia ^{[4
]}

Bacsa, John ^{[1
]}

Mercer, Amy E. ^{[3
]}

Nixon, Gemma ^{[2
]}

Stocks, Paul A. ^{[2
]}

O'Neill, Paul M. ^{[1
]}

机构：

[1] Univ Liverpool, Dept Chem, Liverpool L69 3BX, Merseyside, England

[2] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England

[3] MRC, Ctr Drug Safety Sci, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England

[4] Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England

来源：

ORGANIC & BIOMOLECULAR CHEMISTRY | 2010年 / 8卷 / 09期

基金：

英国生物技术与生命科学研究理事会;

关键词：

HIGHLY STEREOSELECTIVE-SYNTHESIS; ANTIPROLIFERATIVE ACTIVITY; BICYCLIC PEROXIDES; ARTEMISININ; DERIVATIVES; DRUG; METHODOLOGY; MALARIA; DESIGN; POTENT;

D O I：

10.1039/b924319d

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

引用

页码：2068 / 2077

页数：10

共 43 条

[1] Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin [J].

Amewu, Richard ;

Stachulski, Andrew V. ;

Ward, Stephen A. ;

Berry, Neil G. ;

Bray, Patrick G. ;

Davies, Jill ;

Labat, Gael ;

Vivas, Livia ;

O'Neill, Paul M. .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2006, 4 (24) :4431-4436

[2] Synthesis of 1,2,4-trioxepanes via application of thiol-olefin Co-oxygenation methodology [J].

Amewu, Richard ;

Stachulski, Andrew V. ;

Berry, Neil G. ;

Ward, Stephen A. ;

Davies, Jill ;

Labat, Gael ;

Rossignol, Jean-Francois ;

O'Neill, Paul M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (23) :6124-6130

[3] A highly stereoselective synthesis of D-erythrose derivatives by one-carbon homologation of 2,3-O-isopropylidene-D-glyceraldehyde with (R)-methyl p-tolyl sulfoxide [J].

Arroyo-Gómez, Y ;

Rodríguez-Amo, JF ;

Santos-García, M ;

Sanz-Tejedor, MA .

TETRAHEDRON-ASYMMETRY, 2000, 11 (03) :789-796

[4] A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic β-sulfonyl-endoperoxides [J].

Bachi, MD ;

Korshin, EE ;

Hoos, R ;

Szpilman, AM ;

Ploypradith, P ;

Xie, SJ ;

Shapiro, TA ;

Posner, GH .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (12) :2516-2533

[5] Synthesis and reactions of antimalarial bicyclic peroxides [J].

Bachi, MD ;

Korshin, EE ;

Hoos, R ;

Szpilman, AM .

JOURNAL OF HETEROCYCLIC CHEMISTRY, 2000, 37 (03) :639-646

[6] SYNTHESIS OF 1,2,4-TRIOXANES VIA INTRAMOLECULAR OXYMERCURIATION [J].

BLOODWORTH, AJ ;

SHAH, A .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1991, (14) :947-948

[7] Synthesis and in vitro Trichomonacidal activities of some new dialkylperoxides and 1,2,4-trioxanes [J].

Camuzat-Dedenis, B ;

Provot, O ;

Cointeaux, L ;

Perroux, V ;

Berrien, JF ;

Bories, C ;

Loiseau, PM ;

Mayrargue, JL .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2001, 36 (10) :837-842

[8] Synthesis and antimalarial activity of trioxaquine derivatives [J].

Dechy-Cabaret, O ;

Benoit-Vical, F ;

Loup, C ;

Robert, A ;

Gornitzka, H ;

Bonhoure, A ;

Vial, H ;

Magnaval, JF ;

Séguéla, JP ;

Meunier, B .

CHEMISTRY-A EUROPEAN JOURNAL, 2004, 10 (07) :1625-1636

[9]

Dechy-Cabaret O, 2000, CHEMBIOCHEM, V1, P281, DOI 10.1002/1439-7633(20001117)1:4<281::AID-CBIC281>3.3.CO

[10]

2-N

← 1 2 3 4 5 →