RESUMO
Fosmidomycin derivatives in which the hydroxamic acid group has been replaced by several bidentate chelators as potential hydroxamic alternatives were prepared and tested against the DXR from Escherichia coli. These results illustrate the predominant role of the hydroxamate functional group as the most effective metal binding group in DXR inhibitors.
Assuntos
Aldose-Cetose Isomerases/química , Quelantes/química , Inibidores Enzimáticos/química , Fosfomicina/análogos & derivados , Ácidos Hidroxâmicos/química , Aldose-Cetose Isomerases/antagonistas & inibidores , Quelantes/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Fosfomicina/química , Fosfomicina/farmacologia , Concentração Inibidora 50 , Metaloproteínas/química , Estrutura Molecular , Ligação Proteica/efeitos dos fármacosRESUMO
Fosmidomycin and its analogue FR-900098 are potent inhibitors of 1-deoxy-d-xylulose 5-phosphate reducto-isomerase (DXR), the second enzyme of the MEP pathway for the biosynthesis of isoprenoids. This paper describes the synthesis of analogues of the two reverse phosphonohydroxamic acids 3 and 4, in which the length of the carbon spacer is modified, the N-methyl group of 3 is replaced by an ethyl group, and the phosphate group is replaced by potential isosteric moieties, i.e., sulfonate or carboxylate functionalities. The potential of the synthesized analogues to inhibit the E. coli DXR was evaluated.
Assuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Eritritol/análogos & derivados , Fosfomicina/análogos & derivados , Complexos Multienzimáticos/antagonistas & inibidores , Organofosfonatos/química , Oxirredutases/antagonistas & inibidores , Fosfatos Açúcares/metabolismo , Terpenos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Eritritol/química , Eritritol/metabolismo , Fosfomicina/química , Estrutura Molecular , Relação Estrutura-Atividade , Fosfatos Açúcares/química , Terpenos/química , Terpenos/metabolismoRESUMO
Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.