RESUMO
1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative 2c showed potent inhibition of PfIspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with PfIspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg(2+) were determined by X-ray structure analysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds.
Assuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Fosfomicina/análogos & derivados , Aldose-Cetose Isomerases/metabolismo , Domínio Catalítico , Cristalização , Fosfomicina/síntese química , Fosfomicina/farmacologia , NADP/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.
Assuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Anti-Infecciosos/farmacologia , Descoberta de Drogas/métodos , Fosfomicina/análogos & derivados , Aldose-Cetose Isomerases/genética , Aldose-Cetose Isomerases/metabolismo , Sequência de Aminoácidos , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/genética , Fosfomicina/síntese química , Fosfomicina/química , Fosfomicina/farmacologia , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Homologia de Sequência de Aminoácidos , EstereoisomerismoRESUMO
A straightforward, highly stereoselective protocol toward the synthesis of deuterium-labeled (2R,3S,4S)-ß-cyclohexenylserine has been developed. Key steps are a Nozaki-Hiyama-Kishi reaction generating the stereogenic centers and a ring-closing metathesis for the construction of the cyclohexenyl ring system. The labeled amino acid was further activated as an SNAc-ester for feeding experiments.
