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1.
J Med Chem ; 58(4): 2025-35, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25633870

RESUMO

Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.


Assuntos
Antimaláricos/farmacologia , Fosfomicina/análogos & derivados , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fosfomicina/síntese química , Fosfomicina/química , Fosfomicina/farmacologia , Células HeLa , Humanos , Camundongos , Camundongos SCID , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
2.
J Med Chem ; 57(21): 8827-38, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25254502

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-Atividade
3.
J Med Chem ; 55(14): 6566-75, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-22731758

RESUMO

Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted ß-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfomicina/análogos & derivados , Aldose-Cetose Isomerases/antagonistas & inibidores , Aldose-Cetose Isomerases/química , Antiprotozoários/síntese química , Antiprotozoários/metabolismo , Técnicas de Química Sintética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Fosfomicina/síntese química , Fosfomicina/química , Fosfomicina/metabolismo , Fosfomicina/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/química , Oxirredutases/antagonistas & inibidores , Oxirredutases/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Conformação Proteica
4.
J Pept Sci ; 15(11): 783-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19787820

RESUMO

Neuropeptides control numerous physiological processes in insects. The regulation of water balance is a crucial aspect of homeostasis in terrestrial insects and has been shown to be under endocrine control, primarily by corticotrophin releasing factor (CRF)-related peptides and kinins. For helicokinin I, a diuretic neuropeptide from the economically important insect pest Heliothis virescens, detailed structure-activity relationships have been established based on truncated structures, diverse amino acid scans and peptidomimetic analogues. The activities of selected compounds on functional expressed helicokinin receptors are compared with the results of a Malphigian tubule assay. Implications for further peptidomimetic variations are provided.


Assuntos
Insetos/metabolismo , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Ligação Proteica , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-Atividade
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