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1.
Artigo em Inglês | MEDLINE | ID: mdl-36565667

RESUMO

Nearly half of the world's population is at risk of being infected by Plasmodium falciparum, the pathogen of malaria. Increasing resistance to common antimalarial drugs has encouraged investigations to find compounds with different scaffolds. Extracts of Artocarpus altilis leaves have previously been reported to exhibit in vitro antimalarial activity against P. falciparum and in vivo activity against P. berghei. Despite these initial promising results, the active compound from A. altilis is yet to be identified. Here, we have identified 2-geranyl-2', 4', 3, 4-tetrahydroxy-dihydrochalcone (1) from A. altilis leaves as the active constituent of its antimalarial activity. Since natural chalcones have been reported to inhibit food vacuole and mitochondrial electron transport chain (ETC), the morphological changes in food vacuole and biochemical inhibition of ETC enzymes of (1) were investigated. In the presence of (1), intraerythrocytic asexual development was impaired, and according to the TEM analysis, this clearly affected the ultrastructure of food vacuoles. Amongst the ETC enzymes, (1) inhibited the mitochondrial malate: quinone oxidoreductase (PfMQO), and no inhibition could be observed on dihydroorotate dehydrogenase (DHODH) as well as bc1 complex activities. Our study suggests that (1) has a dual mechanism of action affecting the food vacuole and inhibition of PfMQO-related pathways in mitochondria.


Assuntos
Antimaláricos , Artocarpus , Chalconas , Malária Falciparum , Humanos , Plasmodium falciparum , Chalconas/farmacologia , Chalconas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artocarpus/química , Artocarpus/metabolismo , Malatos/metabolismo , Malatos/farmacologia , Malatos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Malária Falciparum/tratamento farmacológico , Mitocôndrias/metabolismo , Quinonas/farmacologia
2.
Parasitol Int ; 85: 102432, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34363974

RESUMO

Microorganisms in nature are highly diverse biological resources, which can be explored for drug discovery. Some countries including Brazil, Columbia, Indonesia, China, and Mexico, which are blessed with geographical uniqueness with diverse climates and display remarkable megabiodiversity, potentially provide microorganismal resources for such exploitation. In this review, as an example of drug discovery campaigns against tropical parasitic diseases utilizing microorganisms from such a megabiodiversity country, we summarize our past and on-going activities toward discovery of new antimalarials. The program was held in a bilateral collaboration between multiple Indonesian and Japanese research groups. In order to develop a new platform of drug discovery utilizing Indonesian bioresources under an international collaborative scheme, we aimed at: 1) establishment of an Indonesian microbial depository, 2) development of robust enzyme-based and cell-based screening systems, and 3) technology transfer necessary for screening, purification, and identification of antimalarial compounds from microbial culture broths. We collected, characterized, and deposited Indonesian microbes. We morphologically and genetically characterized fungi and actinomycetes strains isolated from 5 different locations representing 3 Indonesian geographical areas, and validated genetic diversity of microbes. Enzyme-based screening was developed against two validated mitochondrial enzymes from Plasmodium falciparum, dihydroorotate dehydrogenase and malate:quinone oxidoreductase, while cell-based proliferation assay was developed using the erythrocytic stage parasite of 3D7 strain. More than 17 thousands microbial culture extracts were subjected to the enzyme- and cell-based screening. Representative anti-malarial compounds discovered in this campaign are discussed, including a few isolated compounds that have been identified for the first time as anti-malarial compounds. Our antimalarial discovery campaign validated the Indonesian microbial library as a powerful resource for drug discovery. We also discuss critical needs for selection criteria for hits at each stage of screening and hit deconvolution such as preliminary extraction test for the initial profiling of the active compounds and dereplication techniques to minimize repetitive discovery of known compounds.


Assuntos
Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Descoberta de Drogas , Plasmodium falciparum/efeitos dos fármacos , Indonésia
3.
J Gen Appl Microbiol ; 67(3): 114-117, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33814517

RESUMO

Two Indonesian fungi Aspergillus assiutensis BioMCC-f.T.7495 and Penicillium pedernalense BioMCC-f.T.5350 along with a Japanese fungus Hypomyces pseudocorticiicola FKI-9008 have been found to produce gentisyl alcohol (1), which inhibits Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) with an IC50 value of 3.4 µM. Another Indonesian fungus, Penicillium citrinum BioMCC-f.T.6730, produced an analog of 1, homogentisic acid (4), which also inhibits PfDHODH with an IC50 value of 47.6 µM.


Assuntos
Álcoois Benzílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fungos/química , Ácido Homogentísico/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Álcoois Benzílicos/química , Álcoois Benzílicos/isolamento & purificação , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Fungos/classificação , Ácido Homogentísico/química , Ácido Homogentísico/isolamento & purificação , Concentração Inibidora 50 , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores
4.
J Gen Appl Microbiol ; 66(5): 273-278, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32669511

RESUMO

An Indonesian soil fungus, Talaromyces pinophilus BioMCC-f.T.3979 was cultured to find novel scaffolds of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We obtained altenusin (1), which inhibits PfDHODH, with an IC50 value of 5.9 µM, along with other metabolites: mitorubrinol (2) and mitorubrinic acid (3). Compounds 1 and 2 inhibited PfDHODH but displayed no activity against the human orthologue. They also inhibited P. falciparum 3D7 cell growth in vitro. Compound 3 showed little PfDHODH inhibitory activity or cell growth inhibitory activity.


Assuntos
Antimaláricos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Talaromyces/química , Antimaláricos/química , Antimaláricos/isolamento & purificação , Benzoatos/química , Benzoatos/isolamento & purificação , Benzoatos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/crescimento & desenvolvimento , Microbiologia do Solo , Especificidade da Espécie
5.
Microorganisms ; 8(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32121612

RESUMO

Basal stem rot (BSR), or Ganoderma rot disease, is the most serious disease associated with the oil palm plant of Southeast Asian countries. A basidiomycetous fungus, Ganoderma boninense, is the causative microbe of this disease. To control BSR in oil palm plantations, biological control agents are gaining attention as a major alternative to chemical fungicides. In the course of searching for effective actinomycetes as potential biological control agents for BSR, Streptomyces palmae CMU-AB204T was isolated from oil palm rhizosphere soil collected on the campus of Chiang Mai University. The culture broth of this strain showed significant antimicrobial activities against several bacteria and phytopathogenic fungi including G. boninense. Antifungal and antibacterial compounds were isolated by antimicrobial activity-guided purification using chromatographic methods. Their structures were elucidated by spectroscopic techniques, including Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), Ultraviolet (UV), and Infrared (IR) analyses. The current study isolated new phenyl alkenoic acids 1-6 and three known compounds, anguinomycin A (7), leptomycin A (8), and actinopyrone A (9) as antimicrobial agents. Compounds 1 and 2 displayed broad antifungal activity, though they did not show antibacterial activity. Compounds 3 and 4 revealed a strong antibacterial activity against both Gram-positive and Gram-negative bacteria including the phytopathogenic strain Xanthomonas campestris pv. oryzae. Compounds 7-9 displayed antifungal activity against Ganoderma. Thus, the antifungal compounds obtained in this study may play a role in protecting oil palm plants from Ganoderma infection with the strain S. palmae CMU-AB204T.

6.
Chem Res Toxicol ; 23(3): 630-6, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20055452

RESUMO

4-Oxo-2-hexenal (4-OHE), which forms a 2'-deoxyguanosine (dG) adduct in a model lipid peroxidation system, is mutagenic in the Ames test. It is generated by the oxidation of omega-3 fatty acids and is commonly found in dietary fats, such as fish oil, perilla oil, rapeseed oil, and soybean oil. 4-OHE also forms adducts with 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), and 5-methyl-2'-deoxycytidine (5-Me-dC) in DNA. In this study, we characterized the structures of these adducts in detail. We measured the amounts of 4-OHE-DNA adducts in mouse organs by LC/MS/MS, after 4-OHE was orally administered to mice. The 4-OHE-dA, 4-OHE-dC, 4-OHE-dG, and 4-OHE-5-Me-dC adducts were detected in stomach and intestinal DNA in the range of 0.25-43.71/10(8) bases. After the 4-OHE administration, the amounts of these DNA adducts decreased gradually over 7 days. We also detected 4-OHE-dC in human lung DNA, in the range of 2.6-5.9/10(9) bases. No difference in the 4-OHE adduct levels was detected between smokers and nonsmokers. Our results suggest that 4-OHE-DNA adducts are formed by endogenous as well as environmental lipid peroxides.


Assuntos
Aldeídos/efeitos adversos , Adutos de DNA/análise , Adutos de DNA/metabolismo , Mutagênicos/efeitos adversos , Animais , Bovinos , DNA/metabolismo , Adutos de DNA/química , Feminino , Humanos , Peroxidação de Lipídeos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Conformação de Ácido Nucleico
7.
J Antibiot (Tokyo) ; 57(3): 173-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15152802

RESUMO

Seven new macrolides having a 12-membered ring, which we termed pladienolides, were isolated from the fermentation broth of Streptomyces platensis Mer-11107. Six of the seven pladienolides inhibited hypoxia-induced reporter gene expression controlled by human VEGF promoter with IC50 values of 0.0018-2.89 microM. They also demonstrated growth-inhibitory activity against U251 human glioma cells in vitro. Pladienolides are highly potent inhibitors of both hypoxia signals and cancer cell proliferation, and thus may be useful as antitumor agents.


Assuntos
Antineoplásicos/isolamento & purificação , Fermentação , Macrolídeos/isolamento & purificação , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/genética , Antineoplásicos/classificação , Antineoplásicos/farmacologia , Humanos , Isoenzimas/efeitos dos fármacos , Isoenzimas/genética , Macrolídeos/classificação , Macrolídeos/farmacologia , Streptomyces , Células Tumorais Cultivadas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
8.
J Antibiot (Tokyo) ; 57(2): 97-103, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15112957

RESUMO

In the course of screening program for inhibitors of angiogenesis, novel substances designated as ICM0301A approximately H (1 approximately 8) were isolated from the culture broth of Aspergillus sp. F-1491. ICM0301s inhibited the growth of human umbilical vein endothelial cells (HUVECs) induced by basic fibroblast growth factor (bFGF) with IC50 values of 2.2 approximately 9.3 microg/ml. ICM0301A (1) showed significant anti-angiogenic activity at lower than 10 microg/ml in the angiogenesis model using rat aorta cultured in fibrin gel. ICM0301s showed very low cytotoxicity against various tumor cells. Furthermore, 1CM0301A did not show any toxic symptom in mice by intraperitoneal injection at 100 mg/kg.


Assuntos
Inibidores da Angiogênese/farmacologia , Aspergillus/química , Compostos de Epóxi/farmacologia , Naftalenos/farmacologia , Inibidores da Angiogênese/isolamento & purificação , Inibidores da Angiogênese/toxicidade , Animais , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Aorta/efeitos dos fármacos , Aorta/crescimento & desenvolvimento , Aspergillus/classificação , Aspergillus/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Compostos de Epóxi/isolamento & purificação , Compostos de Epóxi/toxicidade , Fermentação , Fungos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Naftalenos/isolamento & purificação , Naftalenos/toxicidade , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
9.
Appl Environ Microbiol ; 68(6): 2716-25, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12039725

RESUMO

Streptomyces viridosporus A-914 was screened as a producer of an enzyme to effectively form chiral intermediates of 1,4-dihydropyridine calcium antagonists. The supernatant liquid of the growing culture of this strain exhibited high activity for enantioselective hydrolysis of prochiral 1,4-dihydropyridine diesters to the corresponding (4R) half esters. The responsible enzyme (termed DHP-A) was purified to apparent homogeneity and characterized. Cloning and sequence analysis of the gene for DHP-A (dhpA) revealed that the enzyme was a serine protease that is highly similar in both structural and enzymatic feature to SAM-P45, which is known as a target enzyme of Streptomyces subtilisin inhibitor (SSI), from Streptomyces albogriseolus. In a batch reaction test, DHP-A produced a higher yield of a chiral intermediate of 1,4-dihydropyridine than the commercially available protease P6. Homologous or heterologous expression of dhpA resulted in overproduction of the enzyme in culture supernatants, with 2.4- to 4.2-fold higher specific activities than in the parent S. viridosporus A-914. This indicates that DHP-A is suitable for use in reactions forming chiral intermediates of calcium antagonists and suggests the feasibility of developing DHP-A as a new commercial enzyme for use in the chiral drug industry.


Assuntos
Di-Hidropiridinas/metabolismo , Serina Endopeptidases/metabolismo , Streptomyces/enzimologia , Sequência de Aminoácidos , Catálise , Clonagem Molecular , Expressão Gênica , Hidrólise , Conformação Molecular , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/genética , Streptomyces/genética , Especificidade por Substrato
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