RESUMO
A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.
Assuntos
Diterpenos , Quinonas , Extratos Vegetais , Quinonas/farmacologiaRESUMO
Simaomicin alpha shows potent antimalarial activity in vitro and is known to be a cell-cycle effector. As erythrocytic schizogony of Plasmodium correlates with cell cycle events, we investigated the effect of simaomicin alpha on stage development of the malaria parasite Plasmodium falciparum. Simaomicin alpha interferes with normal parasite development in a time and concentration dependent manner. Parasites exposed to 2.5 nM simaomicin alpha at the ring stage or trophozoite stage showed disrupted development and immature schizont-like and segmenter-like forms were observed. However, schizont stage parasites were not affected by 2.5 nM simaomicin alpha. It is unclear whether mitosis involved in sequential parasite development occurred when parasites were exposed to simaomicin alpha at the ring or trophozoite stage. At a concentration of 5.0 nM, simaomicin alpha inhibited merozoite-trophozoite development. This concentration curtails p-LDH activity at all parasite stages, although its impact on the schizont stage is delayed for 24 hours.
Assuntos
Antimaláricos/farmacologia , Isoquinolinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Plasmodium falciparum/citologia , Plasmodium falciparum/crescimento & desenvolvimentoRESUMO
Our on-going screening program to discover new antitrypanosomal antibiotics has been evaluating compounds isolated from soil microorganisms as well as investigating the antibiotic libraries of the Kitasato Institute for Life Sciences and BioFrontier Laboratories of Kyowa Hakko Kogyo Co., Ltd. We have now discovered two compounds, KS-505a and alazopeptin, which exhibit moderate antitrypanosomal characteristics. We report here the in vitro and in vivo antitrypanosomal activities and cytotoxicities of KS-505a and alazopeptin, compared with some commonly-used antitrypanosomal drugs. This is the first report of in vitro and in vivo antitrypanosomal activities of either KS-505a or alazopeptin.
Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Metilglucosídeos/química , Metilglucosídeos/farmacologia , Terpenos/química , Terpenos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Linhagem Celular , Dipeptídeos/toxicidade , Descoberta de Drogas , Feminino , Humanos , Técnicas In Vitro , Metilglucosídeos/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Testes de Sensibilidade Parasitária , Microbiologia do Solo , Terpenos/toxicidade , Tripanossomicidas/toxicidade , Trypanosoma brucei rhodesiense/efeitos dos fármacosRESUMO
More than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the Kitasato Institute for Life Sciences, were screened against African trypanosomes. Ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin A, echinomycin, hedamycin, irumamycin, LL-Z 1272beta, O-methylnanaomycin A, venturicidin A and virustomycin A. Results of the in vitro assays using the GUTat 3.1 strain of Trypanosomal brucei brucei and the STIB900 strain of T. b. rhodesiense are presented. Cytotoxicity was determined using a human MRC-5 cell line. This is the first report of antitrypanosomal activities of the 10 microbial metabolites listed above.
Assuntos
Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Alcinos/química , Alcinos/isolamento & purificação , Alcinos/metabolismo , Alcinos/farmacologia , Animais , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antraquinonas/metabolismo , Antraquinonas/farmacologia , Linhagem Celular , Cromonas/química , Cromonas/isolamento & purificação , Cromonas/metabolismo , Cromonas/farmacologia , Equinomicina/química , Equinomicina/isolamento & purificação , Equinomicina/metabolismo , Equinomicina/farmacologia , Higromicina B/análogos & derivados , Higromicina B/química , Higromicina B/isolamento & purificação , Higromicina B/metabolismo , Higromicina B/farmacologia , Macrolídeos/química , Macrolídeos/isolamento & purificação , Macrolídeos/metabolismo , Macrolídeos/farmacologia , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Microbiologia do Solo , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Venturicidinas/química , Venturicidinas/isolamento & purificação , Venturicidinas/metabolismo , Venturicidinas/farmacologiaRESUMO
Antimalarial activities have been identified in four microbial metabolites through a screening programme of existing compounds in the Kitasato Institute chemical library. Hedamycin showed selective and potent activity against both drug-resistant and drug-sensitive strains of Plasmodium falciparum. Simaomicin alpha exhibited remarkably strong antimalarial activity, although its activity against a drug-resistant strain was weaker than that against a drug-sensitive strain. The antimalarial effects of triacsins C and D are also reported.
Assuntos
Antraquinonas/farmacologia , Antimaláricos/farmacologia , Isoquinolinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Triazenos/farmacologia , Animais , Antraquinonas/química , Resistência a Medicamentos , Isoquinolinas/química , Testes de Sensibilidade Parasitária , Triazenos/químicaRESUMO
During the course of our screening program to discover new antitrypanosomal compounds, 17 known plant aromatic compounds [12 bis(bibenzyls)s and 5 bibenzyls] were evaluated for in vitro activity against Trypanosoma brucei brucei. Sixteen compounds were found to exhibit antitrypanosomal activity. In particular, three compounds, marchantin A (1), plagiochin A (5) and 2(R)-2-isopropenyl-6,7-dihydroxy-4-(2-phenylethyl)dihydrobenzofuran (16) demonstrated moderate selective and potent antitrypanosomal activities in vitro. We detail here the antitrypanosomal properties and cytotoxicities of the compounds in comparison with two commonly used therapeutic drugs, eflornithine and suramin. Our finding represents the first report of the promising trypanocidal activity of these compounds. The research also provides valuable insight into structure-activity relationships and the possible mode of action of the compounds.
Assuntos
Bibenzilas/química , Bibenzilas/farmacologia , Hepatófitas/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Estrutura MolecularRESUMO
During our search to discover new antitrypanosomal compounds, eight known plant compounds (three phenolic compounds and five kawa lactones) were evaluated for in vitro activity against Trypanosoma brucei brucei. Among them, we found two phenolic compounds and three kawa lactones possessing an α-pyrone influenced antitrypanosomal property. In particular, ß-phenethyl caffeate, farnesyl caffeate and dihydrokawain exhibited high or moderate selective and potent antitrypanosomal activity in vitro. We detail here the antitrypanosomal activity and cytotoxicities of the compounds, in comparison with two commonly used antitrypanosomal drugs (eflornithine and suramin). Our findings represent the first report of the promising trypanocidal activity of these compounds.
Assuntos
Kava/química , Lactonas/química , Lactonas/farmacologia , Própole/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Pironas/química , Pironas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
Two new isochromans, panowamycins A and B, were purified by solvent extraction, silica gel and octadecylsilyl silica gel (ODS) column chromatography followed by preparative HPLC, from a culture broth of Streptomyces sp. K07-0010, together with the known compounds NFAT-133, conglobatin, piericidin C series and dinactin. Structures of panowamycins were elucidated as new analogs of NFAT-133 by spectroscopic studies including various NMR experiments. Panowamycins A and B showed moderate antitrypanosomal activity, with IC(50) values of 0.40 and 3.30 µg ml(-1), respectively.
Assuntos
Antiprotozoários/isolamento & purificação , Cromanos/isolamento & purificação , Streptomyces/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Bangladesh , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Humanos , Concentração Inibidora 50 , Microscopia Eletrônica de Varredura , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Infravermelho , Streptomyces/metabolismo , Streptomyces/ultraestrutura , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
During the course of screening to discover antitrypanosomal compounds, 24 known plant terpenes (6 sesquiterpenes, 14 sesquiterpene lactones and 4 diterpenes) were evaluated for in vitro antitrypanosomal activity against Trypanosoma brucei brucei. Among them, 22 terpenes exhibited antitrypanosomal activity. In particular, α-eudesmol, hinesol, nardosinone and 4-peroxy-1,2,4,5-tetrahydro-α-santonin all exhibited selective and potent antitrypanosomal activities in vitro. Detailed here in an in vitro antitrypanosomal properties and cytotoxicities of the 24 terpenes compared with two therapeutic antitrypanosomal drugs (eflornithine and suramin). This finding represents the first report of promising trypanocidal activity of these terpenes. Present results also provide some valuable insight with regard to structure-activity relationships and the possible mode of action of the compounds.
Assuntos
Terpenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Eflornitina/farmacologia , Plantas/química , Relação Estrutura-Atividade , Suramina/farmacologia , Terpenos/química , Terpenos/isolamento & purificação , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
Three novel antitrypanosomal alkaloids, named spoxazomicins A-C, were isolated by silica gel column chromatography and HPLC from the culture broth of a new endophytic actinomycete species, Streptosporangium oxazolinicum K07-0460(T). The structures of the spoxazomicins were elucidated by NMR and X-ray crystal analyses and shown to be new types of pyochelin family antibiotic. Spoxazomicin A showed potent and selective antitrypanosomal activity with an IC50 value of 0.11 µg ml⻹ in vitro without cytotoxicity against MRC-5 cells (IC50=27.8 µg ml⻹).
Assuntos
Actinobacteria/metabolismo , Alcaloides/farmacologia , Oxazóis/farmacologia , Fenóis/farmacologia , Tiazóis/farmacologia , Tripanossomicidas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Linhagem Celular , Cromatografia/métodos , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Concentração Inibidora 50 , Oxazóis/química , Oxazóis/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Sílica Gel , Tiazóis/química , Tiazóis/isolamento & purificação , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
In the course of screening for antimalarial agents, five tropolone compounds were isolated from the culture broth of Penicillium sp. FKI-4410. Two were known compounds, puberulic acid and stipitatic acid. Three were new analogs of puberulic acid, designated viticolins A-C. Among them, puberulic acid exhibited potent antimalarial inhibition, with IC(50) values of 0.01 µg ml(-1) against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. Furthermore, puberulic acid showed weak cytotoxicity against human MRC-5 cells, with an IC(50) value of 57.2 µg ml(-1). The compound also demonstrated a therapeutic effect in vivo, which compared well against the currently used antimalarial drugs, and thus shows promise as a leading candidate for development into a new antimalarial compound.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Penicillium/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/metabolismo , Antimaláricos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Camundongos , Testes de Sensibilidade Parasitária , Plasmodium berghei/patogenicidade , Resultado do TratamentoRESUMO
Two new nucleotide antibiotics, named sinefungin VA and dehydrosinefungin V, were separated by cation exchange column chromatography and purified by HPLC from the culture broth of Streptomyces sp. K05-0178, together with the known antibiotics, sinefungin, dehydrosinefungin and KSA-9342. The structures of the two novel sinefungin analogs were elucidated by spectroscopic studies, including various NMR and advanced peptide chemical methods. Sinefungin VA consists of adenosine and ornithylvalylalanine, whereas dehydrosinefungin V consists of 4',5'-dehydroadenosine and ornithylvaline. Sinefungin VA showed potent antitrypanosomal activity with an IC(50) value of 0.0026 µg ml(-1) in vitro without cytotoxicity against MRC-5 cells. Dehydrosinefungin V showed moderate antitrypanosomal activity (IC(50)=0.15 µg ml(-1)).
Assuntos
Adenosina/análogos & derivados , Streptomyces/metabolismo , Tripanossomicidas/farmacologia , Adenosina/química , Adenosina/isolamento & purificação , Adenosina/farmacologia , Linhagem Celular , Cromatografia por Troca Iônica/métodos , Fermentação , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética/métodos , Análise Espectral/métodos , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
We accomplished the solid-phase total synthesis of malformin C, which is adaptable for the easy preparation of various derivatives. A solid-phase total synthesis of malformin C was achieved by on-resin macrolactamization and disulfide bond formation, with concurrent cleavage from the resin. Antimalarial and antitrypanosomal activities were examined, which helped elucidate partial structure-activity relationships. Results indicate that the disulfide bond is essential and branched amino acids are also crucial components if the compound is to exhibit potent antimalarial and antitrypanosomal properties.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
In the course of our screening for antitrypanosomal compounds from soil microorganisms, as well as from the antibiotics library of the Kitasato Institute for Life Sciences, we found three peptide antibiotics, leucinostatin (A and B), alamethicin I and tsushimycin, which exhibited potent or moderate antitrypanosomal activity. We report here the in vitro and in vivo antitrypanosomal properties and cytotoxicities of leucinostatin A and B, alamethicin I and tsushimycin compared with suramin. We also discuss their possible mode of action. This is the first report of in vitro and in vivo trypanocidal activity of leucinostatin A and B, alamethicin I and tsushimycin.
Assuntos
Alameticina/farmacologia , Antibacterianos/farmacologia , Lipopeptídeos/farmacologia , Paecilomyces/metabolismo , Peptídeos/farmacologia , Tripanossomicidas , Tripanossomíase Africana/tratamento farmacológico , Alameticina/isolamento & purificação , Alameticina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Fermentação , Lipopeptídeos/isolamento & purificação , Lipopeptídeos/uso terapêutico , Camundongos , Camundongos Endogâmicos ICR , Paecilomyces/classificação , Peptídeos/isolamento & purificação , Peptídeos/uso terapêutico , Peptídeos Cíclicos , Suramina/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/parasitologiaRESUMO
Ethyl acetate (EtOAc) extract from the stem bark of Erythrina fusca showed a antimalarial activity against the multi-drug-resistant strain (K1) of Plasmodium falciparum, and six flavonoids, lupinifolin (1), citflavanone (2), erythrisenegalone (3), lonchocarpol A (4), liquiritigenin (5), and 8-prenyldaidzein (6), were isolated from the extract. Diprenylated flavanone 4 showed a notable antimalarial activity (IC(50); 1.6 microg/mL); however 1 and 3 did not show the activity, even though these compounds possessed prenylated substitution.
Assuntos
Antimaláricos/farmacologia , Erythrina/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/isolamento & purificação , Linhagem Celular , Resistência a Múltiplos Medicamentos , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Flavonoides/química , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Isoflavonas/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Parasitária , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Caules de Planta/química , Prenilação , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Ultravioleta , TailândiaAssuntos
Antibacterianos/química , Antibacterianos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Antibacterianos/toxicidade , Linhagem Celular , Humanos , Estrutura Molecular , Peso Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/toxicidadeAssuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/administração & dosagem , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Álcoois Graxos/administração & dosagem , Álcoois Graxos/farmacologia , L-Lactato Desidrogenase/metabolismo , Trofozoítos/efeitos dos fármacosRESUMO
During the screening of antimalarial substances, the 80% EtOH extract from the outer bark of Ochna integerrima Merr. (Ochnaceae) was shown to have a good anti-malarial activity (IC50 value: 6.5 microg/mL) whereas extracts from the inner barks of O.integerrima showed no antimalarial activity. Biflavanone (1), which had not been found previously from a natural plant source, was isolated as a potent antimalarial active ingredient (IC50 value: 80 ng/mL) from the extract of the outer barks. The stereoisomer of 1 ( = compound 2) was also isolated from this plant; however, its activity was significantly lower than that of 1.