Abstract
Rational design and regioselective synthesis of conformationally restricted furan-derived ligands as potential anti-malarial agents
Highlights
Malaria presents major and apparently continuing health challenges worldwide – in Sub-Saharan Africa.[1]
Various human pathogens,[10,11] including P. falciparum, make exclusive use of the non-mevalonate 1deoxy-D-xylulose-5-phosphate (DOXP)/2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for the biosynthesis of isoprenoids. 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), a key enzyme in this pathway, has been validated as a suitable target for therapeutic intervention,[11] and the antibiotic fosmidomycin 1 and its acetyl derivative FR90009811,13 have been shown to inhibit the enzyme. Numerous analogues of these compounds have been developed,[14] and we have reported the synthesis and evaluation of phosphonated N-aryl- and N-heteroarylcarboxamides and (N-arylcarbamoyl)alkylphosphonic acid derivatives[15,16] as fosmidomycin analogues, N-substituted phosphoramidic acid esters as "reverse" fosmidomycin analogues[17] and N-benzylated phosphoramidic acid derivatives as FR900098 analogues.[18]
Some approaches by other groups have focussed on the development of structural analogues of the natural substrate, DOXP 2, as potential DXR inhibitors.[19,20,21]
Summary
Malaria presents major and apparently continuing health challenges worldwide – in Sub-Saharan Africa.[1]. 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), a key enzyme in this pathway, has been validated as a suitable target for therapeutic intervention,[11] and the antibiotic fosmidomycin 1 and its acetyl derivative FR90009811,13 have been shown to inhibit the enzyme. Numerous analogues of these compounds have been developed,[14] and we have reported the synthesis and evaluation of phosphonated N-aryl- and N-heteroarylcarboxamides and (N-arylcarbamoyl)alkylphosphonic acid derivatives[15,16] as fosmidomycin analogues, N-substituted phosphoramidic acid esters as "reverse" fosmidomycin analogues[17] and N-benzylated phosphoramidic acid derivatives as FR900098 analogues.[18] Some approaches by other groups have focussed on the development of structural analogues of the natural substrate, DOXP 2, as potential DXR inhibitors.[19,20,21] We report the regioselective synthesis of conformationally constrained furan-derived ligands, which incorporate structural features of both DOXP and fosmidomycin
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