RESUMO
In order to study the structure-activity relationship of anti-malarial spongean peroxides, several analogues concerning with the 6-methoxyacetyl moiety and the 3-pentyl residue in methyl 2-(3-methoxy-3-pentyl-1,2-dioxan-6-yl)acetate were synthesized and evaluated for anti-malarial activity. The tert-butyl ester analogue 14 showed stability in mouse serum and a high selectivity index against the malaria parasite, Plasmodium falciparum, and the citronellyl analogue 31 exhibited the strongest in vitro anti-malarial activity among them, and the imidazole analogue 25 showed desirable in vivo anti-malarial activity against P. berghei infected mice.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Dioxanos/química , Peróxidos/química , Peróxidos/farmacologia , Animais , Dioxanos/síntese química , Camundongos , Plasmodium/efeitos dos fármacos , Poríferos/química , Relação Estrutura-AtividadeRESUMO
The reactants of an anti-malarial peroxide having a 6-carbomethoxymethyl-3-methoxy-1,2-dioxane moiety treated with FeSO4 were analyzed. For mechanistic study of the anti-malarial peroxide, two biotinylated probes to elucidate the target molecules were designed and synthesized. The two synthesized probes showed potent anti-malarial activity, and one of them was proved to form an irreversible binding with protein in a model experiment.
Assuntos
Antimaláricos/síntese química , Técnicas Biossensoriais , Peróxidos/síntese química , Antimaláricos/farmacologia , Dioxanos/síntese química , Dioxanos/farmacologia , Desenho de Fármacos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Humanos , Modelos Biológicos , Modelos Químicos , Peróxidos/farmacologia , Ligação Proteica , Fatores de TempoRESUMO
The structure-activity relationship of the anti-malarial substance 3 having a 6-carbomethoxymethyl-3-methoxy-1,2-dioxane structure was studied. The ester portion of the peroxide 3, showing little in vivo efficacy in malaria-infected mice in spite of the potent in vitro activity, was hydrolyzed in serum to afford an inactive free acid 4. The amide analogues (8 and 9) robust to mouse serum were disclosed to exhibit in vivo anti-malarial potency.
Assuntos
Antimaláricos/síntese química , Antimaláricos/uso terapêutico , Peróxidos/síntese química , Peróxidos/uso terapêutico , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Camundongos , Poríferos , Relação Estrutura-AtividadeRESUMO
On the basis of a comparative analysis for stability in mouse serum between 15-O-acetylbruceolide and bruceolide 15-methyl carbonate, several 3,15-dialkyl carbonates of bruceolide were synthesized and their in vitro antimalarial activity was assessed. Methyl, ethyl, and isopropyl carbonates with pronounced in vitro activity were further evaluated for in vivo antimalarial potency. Both the methyl and ethyl carbonates significantly increased the life span of mice as compared with 3,15-di-O-accetylbruceolide and chloroquine.
Assuntos
Antimaláricos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Quassinas/síntese química , Animais , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Estabilidade de Medicamentos , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei , Quassinas/farmacologia , Quassinas/toxicidade , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Bioassay-guided separation by use of the fission yeast expressing NES of Rev, a HIV-1 viral regulatory protein, resulted in isolation of valtrate (1) as a new Rev-transport inhibitor from the nucleus to cytoplasm from Valerianae Radix. Valtrate (1) also inhibited the p-24 production of HIV-1 virus without showing any cytotoxicity against the host MT-4 cells.
Assuntos
Transcriptase Reversa do HIV , Iridoides/isolamento & purificação , Iridoides/farmacologia , Inibidores da Transcriptase Reversa/isolamento & purificação , Inibidores da Transcriptase Reversa/farmacologia , Valeriana/química , Biotina , Linhagem Celular , Eletroforese em Gel de Poliacrilamida , Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/farmacologia , Proteína do Núcleo p24 do HIV/biossíntese , Humanos , Inibidores da Transcriptase Reversa/química , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genéticaRESUMO
In an explorative study for new anti-malarial substances using the methyl esters (1 and 2) of peroxyplakoric acids A(3) and B(3) as scaffolds, 6-carbomethoxymethyl-3-methoxy-3-pentyl-1,2-dioxane, which has been readily synthesized from 6-keto-alpha,beta-unsaturated ester, was found to exhibit potent anti-malarial activity with high selective toxicity.
