RESUMO
Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, ß-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3',4'-N-(urenylphenyl)-3-(3â³,4â³,5â³-trimethoxyphenyl)]-2-propen-1-one 5, with a percentage of inhibition of heme polymerization of 87.05 ± 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Chalconas/síntese química , Chalconas/farmacologia , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/química , Chalconas/química , Relação Dose-Resposta a Droga , Heme/antagonistas & inibidores , Heme/síntese química , Heme/química , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Polimerização/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity against cultured Plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and murine malaria model are described. Compounds were prepared via Claisen-Schmidt condensation from available chloromethylphenyl sulfones with substituted aldehydes. Antiplasmodial IC(50) activity of these compounds ranged between 0.025 and 10 microM, those that blocked P. falciparum development at low micro molar concentrations were tested in a murine Plasmodium berghei model, and these compounds delayed the progression of malaria but did not eradicate infections. Much effort and attention are needed for discovery and development of new and less toxic antimalarial drugs.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Chalcona/análogos & derivados , Plasmodium falciparum/efeitos dos fármacos , Sulfonas/síntese química , Sulfonas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Hemeproteínas/metabolismo , Hemoglobinas/metabolismo , Humanos , Hidrólise/efeitos dos fármacos , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei/efeitos dos fármacos , Sulfonas/química , Sulfonas/uso terapêuticoRESUMO
We have synthesized a series of sulfonylureas and have tested their antimalarial activities, including inhibition of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, in vitro hemoglobin hydrolysis, hemozoin formation, and development of Plasmodium berghei in murine malaria. The most active antimalarial compound was (E)-1-[4'-(3-(2,4-difluorophenyl)acryloyl)phenyl]-3-tosylurea (22) with an IC(50) of 1.2microM against cultured P. falciparum parasites. Biological results suggest a fairly potent antimalarial activity for this derivative, but also imply that its activity may arise from an unknown mechanism. Indeed, these compounds may act against malaria parasites through multiple mechanisms.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacologia , Animais , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Malária/tratamento farmacológico , Masculino , Camundongos , Conformação Molecular , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacosRESUMO
Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.
Assuntos
Antimaláricos/síntese química , Chalconas/síntese química , Compostos de Fenilureia/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Chalconas/química , Chalconas/farmacologia , Cisteína Endopeptidases/química , Globinas/metabolismo , Heme/química , Hemeproteínas/síntese química , Hidrólise , Malária/tratamento farmacológico , Camundongos , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Polímeros , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/química , Modelos Animais de Doenças , Hemeproteínas/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hidrólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária , Plasmodium berghei/química , Compostos de Quinolínio/química , Compostos de Quinolínio/metabolismo , Compostos de Quinolínio/farmacologia , Relação Estrutura-Atividade , Taxa de SobrevidaRESUMO
A series of sulfonamide chalcone derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation in vitro and their activity against cultured Plasmodium falciparum parasites. Inhibition of beta-hematin formation was minimal in the aromatic ring of the chalcone moiety as it appeared for compounds 4b, 4d-f, and greatest with compounds 4g (IC50 0.48 microM) and 4k (IC50 0.50 microM) with a substitution of 3,4,5-trimethoxyl and 3-pyridinyl, respectively. In this study, the most active compound resulted 1[4'-N(2'',5''-dichlorophenyl) sulfonyl-amidephenyl]-3-(4-methylphenyl)-2-propen-1-one 4i, effective as antimalarial by the inhibition of cultured P. falciparum parasites (1 microM). These studies open up the novel possibility of development of sulfonamide derivatives as antimalarials that target beta-hematin formation and the inhibition of the development of cultured P. falciparum parasites, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that chalcones exert their antimalarial activity via multiple mechanisms.
Assuntos
Antimaláricos/síntese química , Chalcona/análogos & derivados , Chalcona/síntese química , Plasmodium falciparum/efeitos dos fármacos , Sulfonamidas/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Chalcona/farmacologia , Hemeproteínas/antagonistas & inibidores , Concentração Inibidora 50 , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
This is a general review of currently available antimalarial drugs, these compounds are gathered according with its chemical structure and the biological targets. A great number of these new antimalarial agents are now moving actively in the pipeline from basic science to clinical studies.
Assuntos
Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Malária/tratamento farmacológico , Animais , Artemisininas/uso terapêutico , Fatores Biológicos/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Inibidores de Proteases/uso terapêutico , Quinina/análogos & derivados , Quinina/uso terapêutico , Sesquiterpenos/uso terapêuticoRESUMO
El presente estudio, es parte de un programa de investigación de la vida marina en la costa de Venezuela, donde fueron identificados varios derivados prostanoicos extraídos del coral blando Plexaura homomalla y se hicieron algunas modificaciones quimicas a la estructura del intermediario PGA. 2.
Assuntos
Animais , Prostaglandinas , QuímicaRESUMO
En este trabajo se presenta la síntesis de algunos éteres cíclicos prostanoides, análogos de la prostaciclina obtenidos partiendo del intermediario PGA2 (extraído del coral blando Plexura homomalla, recolectado en la costa note de Venezuela); conjuntamente con algunas pruebas farmacológicas preminares en el área de inmunología o hematología