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1.
M.M.O. Cabral J.M. Barbosa-Filho M.C.O. Chaves W. De Souza 《Experimental parasitology》2010,124(3):319-7054
Trypanosoma cruzi is the ethiological agent for Chagas disease in Latin America. This study aimed to test the trypanocidal effect of licarin A and burchellin isolated from plants in northeastern Brazil. These neolignans were tested on T. cruzi and on peritoneal macrophages, to evaluate drug toxicity. Epimastigote growth was inhibited in 45% with licarin A and 20% with burchellin with an IC50/96 h of 462.7 μM and 756 μM, respectively. Epimastigotes treated with licarin A presented swollen mitochondria and disorganized mitochondrial cristae, kDNA and Golgi complex. When treated with burchellin, they presented enormous autophagosomes and chromatin disorganization. Licarin A and burchellin were able to induce trypomastigote death with IC50/24 h of 960 μM and 520 μM, respectively. Although licarin A presented an IC50 for trypomastigotes higher than for epimastigotes, both substances acted as therapeutic trypanocidal agents, because they were able to kill parasites without affecting macrophages. Due to our results, burchellin and licarin A need to be further analysed to observe if they may be used as alternative blood additive prophylaxis against Chagas disease, since it has been established that blood transfusion is an important mechanism in the transmission process. 相似文献
2.
Erika Gracielle Pinto Daniel C. Pimenta Marta Maria Antoniazzi Carlos Jared Andre Gustavo Tempone 《Experimental parasitology》2013
Nature has provided inspiration for Drug Discovery studies and amphibian secretions have been used as a promising source of effective peptides which could be explored as novel drug prototypes for neglected parasitic diseases as Leishmaniasis and Chagas disease. In this study, we isolated four antimicrobial peptides (AMPs) from Phyllomedusa nordestina secretion, and studied their effectiveness against Leishmania (L.) infantum and Trypanosoma cruzi. The antiparasitic fractions were characterized by mass spectrometry and Edman degradation, leading to the identification of dermaseptins 1 and 4 and phylloseptins 7 and 8. T. cruzi trypomastigotes were susceptible to peptides, showing IC50 values in the range concentration of 0.25–0.68 μM. Leishmania (L.) infantum showed susceptibility to phylloseptin 7, presenting an IC50 value of 10 μM. Except for phylloseptin 7 which moderate showed cytotoxicity (IC50 = 34 μM), the peptides induced no cellular damage to mammalian cells. The lack of mitochondrial oxidative activity of parasites detected by the MTT assay, suggested that peptides were leishmanicidal and trypanocidal. By using the fluorescent probe SYTOX® Green, dermaseptins 1 and 4 and phylloseptins 7 and 8 showed time-dependent plasma membrane permeabilization of T. cruzi; phylloseptin 7 also showed a similar effect in Leishmania parasites. The present study demonstrates for the first time that AMPs target the plasma membrane of Leishmania and T. cruzi, leading to cellular death. Considering the potential of amphibian peptides against protozoan parasites and the reduced mammalian toxicity, they may contribute as scaffolds for drug design studies. 相似文献
3.
Trypanosoma cruzi is the causative agent of Chagas disease which affects 8 million people in Latin America. The parasite possesses high capacity to evade host immune system and the available drugs to treat Chagas disease present low efficacy combined to serious side effects to patients. Therefore, the identification of alternative therapeutics is essential. Brazilian flora exhibits an immense diversity of metabolites with great potential to be developed into new drugs. We investigated the action of 2″,3″-dihydroochnaflavone a biflavonoid extracted from Luxemburgia nobilis Eichler ex Engl. (Ochnaceae) against T. cruzi (Y strain). Our experiments showed that this compound is effective against parasite epimastigote forms, presenting IC50 value of (2.5 ± 0.1) μM after 96 h of treatment. Ultrastructure alterations were also detected in treated epimastigotes especially mitochondrial enlargement at the kinetoplast region. At the concentration of 30 μM, the compound killed (61.6 ± 3.37)% of the parasite in its amastigote form. In addition, at the same concentration, the compound killed all trypamastigotes growing within murine macrophages after 7–9 days of infection. Nonetheless, the biflavonoid concentrations were harmless to murine enriched population of lymphocytes and peritoneal macrophages. These results indicate that 2″,3″- dihydroochnaflavone presents activity against T. cruzi. 相似文献
4.
Babesia gibsoni is mainly transmitted by hard ticks of the genus Rhipicephalus (R. sanguineus) and Haemaphysalis (H. longicornis), and causes canine babesiosis. Clinical manifestations of B. gibsoni infection include fever, hemoglobinemia, hemoglobinuria, and progressive anemia. Traditional antibabesial therapy, such as imidocarb dipropionate or diminazene aceturate, can only alleviate severe clinical manifestations and cannot eliminate parasites in the host. Food and Drug Administration (FDA)-approved drugs are a solid starting point for researching novel therapy strategies for canine babesiosis. In this work, we screened 640 FDA-approved drugs against the growth of B. gibsoni in vitro. Among them, 13 compounds (at 10 μM) exhibited high growth inhibition (>60%), and two compounds, namely idarubicin hydrochloride (idamycin) and vorinostat, were chosen for further investigation. The half-maximal inhibitory concentration (IC50) values of idamycin and vorinostat were determined to be 0.044 ± 0.008 μM and 0.591 ± 0.107 μM, respectively. Viability results indicated that a concentration of 4 × IC50 of vorinostat prevented the regrowth of treated B. gibsoni, whereas parasites treated with 4 × IC50 concentration of idamycin remained viable. The B. gibsoni parasites treated with vorinostat exhibited degeneration within erythrocytes and merozoites, in contrast to the oval or signet-ring shape of normal B. gibsoni parasites. In conclusion, FDA-approved drugs offer a valuable platform for drug repositioning in antibabesiosis research. Particularly, vorinostat demonstrated promising inhibitory effects against B. gibsoni in vitro, and further studies on vorinostat are necessary to elucidate its mechanism as a novel treatment in infected animal models. 相似文献
5.
《Bioorganic & medicinal chemistry》2016,24(18):4228-4240
In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03 μM. The 8c derivative showed the highest potency against cruzain (IC50 = 2.4 μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb = −7.39 kcal·mol−1) indicates interaction (via dipole–dipole) between the hybridized sulfur sp3 atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease. 相似文献
6.
Yusuf Scak Emine Elin Oru‐Emre Mehmet
ztürk Tuba Takn‐Tok Ayegül Karaküük‐Iyidoan 《Chirality》2019,31(8):603-615
In this study, a series of fluorine‐containing chiral hydrazide‐hydrazone derivatives [III‐XII] from ?‐cysteine ethyl ester hydrochloride was synthesized as new antioxidant and anticholinesterase agents. The antioxidant activity of these derivatives was evaluated by ABTS+· and DPPH· scavenging and CUPRAC assays and the anticholinesterase activity by the Ellman method spectrophotometrically. The results of the antioxidant assay showed that compounds V , IX , and X exhibited higher activity than BHT and α‐tocopherol used as positive standards. Among the synthesized derivatives, compound IX (IC50: 2.3 ± 1.6 μM) exhibited higher acetylcholinesterase inhibitory activity than galantamine (IC50: 4.5 ± 0.8 μM). Compounds XI (IC50: 9.6 ± 1.0 μM), IX (IC50: 12.5 ± 1.6 μM), III (IC50: 16.0 ± 1.6 μM), X (IC50: 17.2 ± 1.8 μM), VI (IC50: 20.2 ± 0.8 μM), XII (IC50: 21.5 ± 1.0 μM), and VII (IC50: 24.6 ± 0.6 μM) displayed better butyrylcholinesterase inhibitory activity than galantamine (IC50: 46.03 ± 0.14 μM). ADME‐Tox analysis was used to probe the drug‐like properties of the compounds. Molecular docking studies were also applied to understand the interactions between compounds and targets. The docking calculations were supported by the experimental data. In particular, compound IX , having better activity than galantamine against acetylcholinesterase and butyrylcholinesterase enzymes, was visualized using molecular docking. 相似文献
7.
Benítez J Becco L Correia I Leal SM Guiset H Pessoa JC Lorenzo J Tanco S Escobar P Moreno V Garat B Gambino D 《Journal of inorganic biochemistry》2011,105(2):303-312
In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [VIVO(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC50 values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC50 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC50 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC50 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC50 values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells. 相似文献
8.
《Phytochemistry》2012
Chemical investigation of the leaves of the oriental medicinal plant Aglaia odorata resulted in the isolation of five compounds: two dolabellane diterpenoids, two dammarane triterpenoids and a protostane triterpenoid, along with twenty known compounds. Their structures were elucidated on the basis of extensive spectroscopic analysis and by comparison of their NMR spectroscopic data with those reported in the literature. The anti-inflammatory activities of all compounds were evaluated as inhibitory activities against lipopolysaccharide (LPS) induced nitric oxide (NO) production in RAW264.7 cell lines. Eleven compounds possessed potent nitric oxide inhibitory activity with IC50 values ranging from 2.1 to 14.2 μM, these being better than that of the positive control, indomethacin (IC50 = 14.5 μM). In addition, three compounds exhibited significant activity against PGE2 release with IC50 values of 2.6, 16.1 and 23.0 μM. 相似文献
9.
Metacytofilin (MCF) was isolated from the fungus Metarhizium sp. TA2759. Although MCF possesses anti-Toxoplasma activity, the effects of this compound against other parasites are unknown. Here, we evaluated the in vitro anti-malarial activity of MCF against the 3D7 strain and the chloroquine-resistant K1 strain of Plasmodium falciparum. The half maximal inhibitory concentrations (IC50) of MCF against the 3D7 and K-1 strains following culture for 48 h were 666 nM and 605 nM, respectively. Artemisinin was more potent than MCF against both strains (3D7 IC50: 17.4 nM; K-1 IC50: 18.3 nM), while chloroquine was ineffective against the chloroquine-resistant strain (3D7 IC50: 39.1 nM; K-1 IC50: 1.62 μM). MCF affected the ring stage of the parasites, resulting in their death as shown by spots within red blood cells. MCF also inhibited parasite growth following culture for 72 h (3D7 IC50, 285 nM). Four optical isomers of cyclo[Leu-Phe]-diketopiperazine derivatives with modified methoxy and/or hydroxyl groups lost anti-malarial activity, suggesting that the spatial positions of the methoxy and hydroxyl groups in MCF play an important role in its anti-malarial effects. Together, these data suggest that MCF may represent a promising lead compound for treatment of drug-resistant malarial parasites. 相似文献
10.
Feifei Li Qian Sun Lili Hong Lingzhi Li Yingying Wu Mingyu Xia Takshi Ikejima Ying Peng Shaojiang Song 《Bioorganic & medicinal chemistry letters》2013,23(9):2500-2504
Four new daphnane-type diterpenes, genkwadanes A–D (1–4), together with 19 known ones, were isolated from ethanol extract of the flower buds of Daphne genkwa. Their structures were determined on the basis of extensive spectroscopic data. Among them, daphnane-type diterpene with a 1,10-double bond (1) was isolated from this plant for the first time. The cytotoxicity of all compounds 1–23 against the 10 selected human cancer cell lines was assayed. A number of compounds exhibited significant activities against the 10 cancer cell lines (IC50 < 9.56 μM). and most interestingly, all the compounds revealed preferred cytotoxicities on the HT-1080 cell line and displayed much stronger inhibitory activities (IC50 < 29.94 μM) compared with positive control 5-fluorouracil (IC50 = 35.62 μM), particularly, compounds 9–11, 13, 16 and 19 exhibited the strongest cytotoxicity activities against the HT-1080 cell line (IC50 < 0.1 μM). 相似文献
11.
179 compounds in a Mongolian compound library were investigated for their inhibitory effect on the in vitro growth of Plasmodium falciparum and Toxoplasma gondii. Among these compounds, brachangobinan A at a half-maximal inhibition concentration (IC50) of 2.62 μM and a selectivity index (SI) of 27.91; 2-(2′-hydroxy-5′-O-methylphenyl)-5-(2″,5″-dihydroxyphenyl)oxazole (IC50 3.58 μM and SI 24.66); chrysosplenetin (IC50 3.78 μM and SI 15.26); 4,11-di-O-galloylbergenin (IC50 3.87 μM and SI 13.38); and 2-(2′,5′-dihydroxyphenyl)-5-(2″-hydroxyphenyl)oxazole (IC50 6.94 μM and SI 11.48) were identified as potential inhibitors of P. falciparum multiplication. Additionally, tricin (IC50 12.94 μM and SI > 23.40) was identified as a potential inhibitor of T. gondii multiplication. Our findings represent a good starting point for developing novel antimalarial and anti-Toxoplasma therapeutics from Mongolian compounds. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(12):2768-2772
Novel hydroxylated benzylideneamino imidazole derivatives were synthesized and their radical scavenging activity was assessed against DPPH and hydroxyl radicals. In the DPPH assay, most of the synthesized compounds showed an IC50 in the range 3.2 μM ⩽ IC50 ⩽ 8.4 μM, lower than the reference compound trolox (IC50 = 9.5 μM) or the parent aldehydes (5.4 μM ⩽ IC50 ⩽ 11.6 μM). The activity depends mainly on the phenolic subunit (number and position of the hydroxyl groups) and the extent of conjugation with the imidazole ring. In the deoxyribose assay, all the compounds, including parent imidazoles and aldehydes, showed high activity against the hydroxyl radical and the ability to chelate iron ions. At 5 μM concentration, the compounds protected the deoxyribose from degradation by hydroxyl radical between 62% and 38%. 相似文献
13.
Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC50 values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC50 values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC50 = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC50 values ranging between (2.54–14.95 μM) and IC90 values ranging between (11.90–19.47 μM), using pentamidine as a control (IC50 values 2.09 ≥ 16.8 μM) and IC90 values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC50 values ranging between (0.39–7.12 μM) and IC90 values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC50 and IC90values 11.82 and 30.82 μM). 相似文献
14.
《Phytomedicine》2014,21(5):676-681
Leishmaniasis and Chagas disease are infectious diseases caused by parasite Leishmania sp. and Trypanosoma cruzi, respectively, and are included among the most neglected diseases in several underdeveloped and developing countries, with an urgent demand for new drugs. Considering the antiparasitic potential of MeOH extract from leaves of Casearia sylvestris Sw. (Salicaceae), a bioguided fractionation was conducted and afforded four active clerodane diterpenes (casearins A, B, G, and J). The obtained results indicated a superior efficacy of tested casearins against trypomastigotes of T. cruzi, with IC50 values ranging from 0.53 to 2.77 μg/ml. Leishmania infantum promastigotes were also susceptible to casearins, with IC50 values in a range between 4.45 and 9.48 μg/ml. These substances were also evaluated for mammalian cytotoxicity against NCTC cells resulting in 50% cytotoxic concentrations (CC50) ranging from 1.46 to 13.76 μg/ml. Additionally, the action of casearins on parasite membranes was investigated using the fluorescent probe SYTOX Green. The obtained results demonstrated a strong interaction of casearins A and B to the plasma membrane of T. cruzi parasites, corroborating their higher efficacy against these parasites. In contrast, the tested casearins induced no alteration in the permeability of plasma membrane of Leishmania parasites, suggesting that biochemical differences between Leishmania and T. cruzi plasma membrane might have contributed to the target effect of casearins on trypomastigotes. Thus, considering the importance of studying novel and selective drug candidates against protozoans, casearins A, B, G, and J could be used as tools to future drug design studies. 相似文献
15.
Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC50 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC50 values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2020,30(12):127175
Novel nucleoside analogues named “triazoxins” were synthesized. Of these, two analogues were found to be highly effective against Giardia lamblia, an intestinal parasite and a major cause of waterborne infection, worldwide. While compound 7 reduced the growth of trophozoites in culture (IC50, ~5 μM), compound 21 blocked the in vitro cyst production (IC50 ~5 μM). Compound 21 was also effective against trophozoites (IC50, ~36 μM). A third analogue (compound 8) was effective against both trophozoites (IC50, ~36 μM) and cysts (IC50, ~20 μM) although at higher concentration. Thus triazoxin analogues are unique and exhibit morphology (i.e., trohozoites or cysts) -specific effects against Giardia. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(12):2764-2767
A series of 6-nitro-3-(m-tolylamino) benzo[d]isothiazole 1,1-dioxide analogues were synthesized and evaluated for their inhibition activity against 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES-1). These compounds can inhibit both enzymes with IC50 values ranging from 0.15 to 23.6 μM. One of the most potential compounds, 3g, inhibits 5-LOX and mPGES-1 with IC50 values of 0.6 μM, 2.1 μM, respectively. 相似文献
18.
Bin Sun Juma Hoshino Katie Jermihov Laura Marler John M. Pezzuto Andrew D. Mesecar Mark Cushman 《Bioorganic & medicinal chemistry》2010,18(14):5352-5366
A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 μM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer. 相似文献
19.
Ozlem Demirkiran 《Phytochemistry letters》2012,5(4):700-704
Purification of n-BuOH fraction from 80% ethanol extract of Hypericum thasium Griseb. resulted in the isolation of three new compounds 3′,4,5′-trihydroxy-6-methoxy-2-O-α-l-arabinosylbenzophenone (1), 3′,4,5′,6-tetrahydroxy-2-O-α-l-arabinosylbenzophenone (2), and 3′,4-dihydroxy-5′-methoxy-2-O-α-l-arabinosyl-6-O-β-d-xylosylbenzophenone (3) along with a known flavonoid glycoside quercetin-3-O-α-l-arabinofuranoside (4). The structures of the new compounds were elucidated by 1D and 2D NMR analysis as well as HRESIMS. The isolated compounds (1–4), as well as quercetin, and kaempferol previously isolated from EtOAc fraction were screened against MAO-A inhibitory activity. When tested against the MAO-A quercetin and kaempferol displayed IC50 values of 19.6, and 17.5 μM, respectively. The IC50 values for MAO-A inhibition by compounds (1–4) were 310.3, 111.2, 726.0, and 534.1 μM, respectively. Standard inhibitor (clorgyline) exhibited MAO-A inhibition with an IC50 value of 0.5 μM. 相似文献
20.
《Bioorganic & medicinal chemistry letters》2014,24(9):2202-2205
Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC50 = 4.24 μM) and 18d (IC50 = 2.75 μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC50 = 4.99 μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC50 = 2.78 μM) and CDDO-Me (IC50 = 5.85 μM), particularly, 10b (IC50 = 0.02 μM) presented the strongest effect, which was selected as a candidate for further study. 相似文献