共查询到20条相似文献,搜索用时 31 毫秒
1.
Inhibition of Bacillus anthracis metallo-β-lactamase by compounds with hydroxamic acid functionality
Sung-Kun Kim Mara Demuth Sara R. Schlesinger Sung Joon Kim Jonathan Urbanczyk Robert W. Shaw 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):132-137
AbstractMetallo-β-lactamases (MBLs) that catalyze hydrolysis of β-lactam antibiotics are an emerging threat due to their rapid spread. A strain of the bacterium Bacillus anthracis has its ability to produce and secrete a MBL, referred to Bla2. To address this challenge, novel hydroxamic acid-containing compounds such as 3-(heptyloxy)-N-hydroxybenzamide (compound 4) and N-hydroxy-3-((6-(hydroxyamino)-6-oxohexyl)oxy)benzamide (compound 7) were synthesized. Kinetic analysis of microbial inhibition indicated that the both sides of hydroxamic acids containing compound 7 revealed a reversible, competitive inhibition with a Ki value of 0.18?±?0.06?μM. The result has reflected that the both sides of dihydroxamic acids in a molecule play a crucial role in the binding affinity rather than monohydroxamic containing compound 4 which was unable to inhibit Bla2. In addition, in silico analysis suggested that compound 7 was coordinated with a zinc ion in the active site of enzyme. These observations suggest that the dihydroxamic acid-containing compound may be a promising drug candidate, and a further implication for designing new inhibitors of Bla2. 相似文献
2.
En Zhang Ming-Ming Wang Shu-Chao Huang Shuai-Min Xu De-Yun Cui Yuan-Li Bo Peng-Yan Bai Yong-Gang Hua Chun-Ling Xiao Shangshang Qin 《Bioorganic & medicinal chemistry letters》2018,28(2):214-221
The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the β-lactam antibiotics, the metallo-β-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of blaNDM-1. The compound 5 was non-hemolytic, even at a concentration of 1000?µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63?±?1.27?μM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs. 相似文献
3.
Xianling Ning Hailong Qi Ridong Li Yan Jin Michael A. McNutt 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):126-129
The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50?=?1.05?±?0.17 µM) and 3h (IC50?=?0.96?±?0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50?=?2.95?±?0.53 µM) and the known PKM2 inhibitor shikonin (IC50?=?8.82?±?2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells. 相似文献
4.
Seung Cheol Baek Hyung Won Ryu Myung-Gyun Kang Hanna Lee Daeui Park Myoung-Lae Cho Sei-Ryang Oh Hoon Kim 《Bioorganic & medicinal chemistry letters》2018,28(14):2403-2407
Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55?µM. Chelerythrine was a reversible competitive MAO-A inhibitor (Ki?=?0.22?µM) with a potency much greater than toloxatone (IC50?=?1.10?µM), a marketed drug. Other isoquinoline alkaloids tested did not effectively inhibit MAO-A or MAO-B. A structural comparison with corynoline suggested the 1- and/or 2-methoxy groups of chelerythrine increase its inhibitory activity against MAO-A. Molecular docking simulations revealed that the binding affinity of chelerythrine for MAO-A (?9.7?kcal/mol) was greater than that for MAO-B (?4.6?kcal/mol). Docking simulation implied that Cys323 and Tyr444 of MAO-A are key residues for hydrogen-bond interaction with chelerythrine. Our findings suggest chelerythrine is one of the most reversible selective and potent natural inhibitor of MAO-A, and that it be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors. 相似文献
5.
Seung Cheol Baek Hyun Woo Lee Hyung Won Ryu Myung-Gyun Kang Daeui Park Soo Hyun Kim Myoung-Lae Cho Sei-Ryang Oh Hoon Kim 《Bioorganic & medicinal chemistry letters》2018,28(4):584-588
Hispidol, an aurone, isolated from Glycine max Merrill, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A), with an IC50 value of 0.26?µM, and to inhibit MAO-B, but with lower potency (IC50?=?2.45?µM). Hispidol reversibly and competitively inhibited MAO-A with a Ki value of 0.10?µM with a potency much greater than toloxatone (IC50?=?1.10?µM), a marketed drug. It also reversibly and competitively inhibited MAO-B (Ki?= 0.51?µM). Sulfuretin, an analog of hispidol, effectively inhibited MAO-A (IC50?=?4.16?µM) but not MAO-B (IC50?>?80?µM). A comparison of their chemical structures showed that the 3′-hydroxyl group of sulfuretin might reduce its inhibitory activities against MAO-A and MAO-B. Flexible docking simulation revealed that the binding affinity of hispidol for MAO-A (?9.1?kcal/mol) was greater than its affinity for MAO-B (?8.7?kcal/mol). The docking simulation showed hispidol binds to the major pocket of MAO-A or MAO-B. The findings suggest hispidol is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a novel lead compound for development of novel reversible inhibitors of MAO-A. 相似文献
6.
Emanuela Berrino Murat Bozdag Sonia Del Prete Fatmah A. S. Alasmary Linah S. Alqahtani Zeid AlOthman 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):1194-1198
The inhibition of α-, β-, γ-, and δ-class carbonic anhydrases (CAs, EC 4.2.1.1) from bacteria (Vibrio cholerae and Porphyromonas gingivalis) and diatoms (Thalassiosira weissflogii) with a panel of N’-aryl-N-hydroxy-ureas is reported. The α-/β-CAs from V. cholerae (VchCAα and VchCAβ) were effectively inhibited by some of these derivatives, with KIs in the range of 97.5?nM – 7.26?µM and 52.5?nM – 1.81?µM, respectively, whereas the γ-class enzyme VchCAγ was less sensitive to inhibition (KIs of 4.75 – 8.87?µM). The β-CA from the pathogenic bacterium Porphyromonas gingivalis (PgiCAβ) was not inhibited by these compounds (KIs?>?10?µM) whereas the corresponding γ-class enzyme (PgiCAγ) was effectively inhibited (KIs of 59.8?nM – 6.42?µM). The δ-CA from the diatom Thalassiosira weissflogii (TweCAδ) showed effective inhibition with these derivatives (KIs of 33.3?nM – 8.74?µM). As most of these N-hydroxyureas are also ineffective as inhibitors of the human (h) widespread isoforms hCA I and II (KIs?>?10?µM), this class of derivatives may lead to the development of CA inhibitors selective for bacterial/diatom enzymes over their human counterparts and thus to anti-infectives or agents with environmental applications. 相似文献
7.
Guangcheng Wang Wenjing Liu Zipeng Gong Yong Huang Yongjun Li 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):139-144
Abstract A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42?±?0.15?µM, as compared to cisplatin (IC50?=?15.24?±?1.27?µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4?µM, which was slightly more active than the reference compound colchicine (IC50?=?10.6?µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin. 相似文献
8.
Xiao-Chun Yang Shi-Jing Qian Li Wang Si-Da Liao Ji Cao Yong-Zhou Hu Qiao-Jun He Hong Zhu Bo Yang 《Translational oncology》2013,6(1):75-82
A novel VP-16 derivative, 4β-[N -(4?-acetyloxyl-phenyl-1?-carbonyl)-4″-aminoanilino]-4′-O-demethyl-4-desoxypodophyllotoxin (GL3), displayed a wide range of cytotoxicity in a panel of human tumor cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 0.82 to 4.88 µM, much less than that of VP-16 (4.18–39.43 µM). Importantly, GL3 induces more significant apoptosis and cell cycle arrest than VP-16. The molecular and cellular machinery studies showed that GL3 functions as a topoisomerase II (Top 2) poison through direct binding to the enzyme, and the advanced cell-killing activities of GL3 were ascribed to its potent effects on trapping Top 2-DNA cleavage complex, Moreover, GL3-triggered DNA double-strand breaks and apoptotic cell death were in a Top 2-dependent manner, because the catalytic inhibitor aclarubicin attenuated these biologic consequences caused by Top 2 poisoning in GL3-treated cells. Taken together, among a series of 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin analog, GL3 stood out by its improved anticancer activity and well-defined Top 2 poisoning mechanisms, which merited the potential value of GL3 as an anticancer lead compound/drug candidate deserving further development. 相似文献
9.
Pyruvate kinase isoenzyme M2 (PKM2) is one of the most important control point enzyme in glycolysis pathway. Hence, its inhibitors and activators are currently considered as the potential anticancer agents. The effect of 28 polyphenolic compounds on the enzyme activity was investigated in vitro. Among these compounds, neoeriocitrin, (?)-catechin gallate, fisetin, (±)-taxifolin and (?)-epicatechin have the highest inhibition effect with IC50 value within 0.65–1.33?µM range. Myricetin and quercetin 3-β-d-glucoside exhibited the highest activation effect with 0.51 and 1.34?µM AC50 values, respectively. Twelve of the compounds showed inhibition effect within 7–38?µM range of IC50 value. Sinapinic acid and p-coumaric acid showed an activation effect with 26.2 and 22.2?µM AC50 values, respectively. The results propose that the polyphenolics may be the potential PKM2 inhibitors/activators, and they may be used as lead compounds for the synthesis of new inhibitors or activators of this enzyme. 相似文献
10.
Wandong Liu Caiyun Hou Yanchun Zhang Mengqi Hu 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):187-198
Abstract Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95?µM) and COX-2 (IC50=0.036?µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug. 相似文献
11.
12.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):997-1001
A new cinnamic acid derivative was isolated from the whole plant of Viola betonicifolia as off white needle. On the basis of various modern spectroscopic techniques including HREI–MS and 1D and 2D NMR, its structure was elucidated as 2,4-dihydroxy, 5-methoxy-cinnamic acid. It showed marked inhibition against DPPH (diphenyl-2-picryl hydrazyl) free radicals with IC50 = 124?±?5.76 µM. The antioxidant property of the compound was compared with α-tocopherole and vitamin C having IC50 values 96?±?0.46 and 90?±?0.56 µM, respectively. In case of antiglycation assay, the compound exhibited moderate activity (IC50 = 355?±?7.56 µM) similar to standard compound, rutin (IC50 = 294?±?0.56 µM). However, it was non-toxic to PC-3 cell line. It is concluded that 2,4-dihydroxy, 5-methoxy-cinnamic acid has antiglycation potential which was further augmented by its antioxidant activity and thus offered an ideal natural therapeutic option for the effective management of diabetes. 相似文献
13.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):717-726
Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50?=?2.51?±?0.2 µM) showed similar inhibitory effect compared with control compound Bestatin (IC50?=?6.25?±?0.4 µM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future. 相似文献
14.
Zixin Xie Donghua Cheng Lu Luo Guoliang Shen Suwei Pan Yaqian Pan 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):905-919
A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36?±?0.27?µM, 1.25?±?0. 23?µM, 2.31?±?0.41?µM, 2.14?±?0.36?µM and 1.85?±?0.32?µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1. 相似文献
15.
Shengqiang Shen Wei Chen Lili Dong Huizhe Lu 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):445-452
GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki?=?0.91?µM against hsHexB; Ki?>?100?µM against hOGA) and compound 15b (Ki?=?3.76?µM against hOGA; Ki?=?30.42?µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors. 相似文献
16.
Simone Tasca Cargnin Andressa Finkler Staudt Patrícia Medeiros Daniel de Medeiros Sol Sol Ana Paula de Azevedo dos Santos Fernando Berton Zanchi Grace Gosmann Antonio Puyet Carolina Bioni Garcia Teles Simone Baggio Gnoatto 《Bioorganic & medicinal chemistry letters》2018,28(3):265-272
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50?=?3.4?µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50?>?400?µM), showing selectivity towards parasites (selectivity index?>?117.47). In combination with artemisinin, compound 7b showed an additive effect (CI?=?1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of ?7.02?kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50?=?93?µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources. 相似文献
17.
Rati K. P. Tripathi Vishnu M. Sasi Sukesh K. Gupta Sairam Krishnamurthy 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):37-57
A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC50?=?0.212?µM, SI?=?331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50?=?0.264?µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50?=?0.024?µM) emerged as lead AChE and BuChE inhibitors respectively; with activity of compound 21 almost equivalent to tacrine. Kinetic studies indicated that compound 4 exhibited competitive and reversible MAO-B inhibition while compounds 21 and 17 showed mixed-type of AChE and BuChE inhibition respectively. Docking studies revealed that these compounds were well-accommodated within MAO-B and ChE active sites through stable hydrogen bonding and/or hydrophobic interactions. This study revealed the requirement of small heteroaryl ring at amino terminal of semicarbazone template for preferential inhibition and selectivity towards MAO-B. Our results suggest that 5-nitrothiazole derived semicarbazones could be further exploited for its multi-targeted role in development of anti-neurodegenerative agents.A library of 2-amino-5-nitrothiazole derived semicarbazones (4–21) was designed, synthesised and evaluated for in vitro MAO and ChE inhibitory activity. Compounds 4, 21 and 17 (shown) have emerged as lead MAO-B (IC50:0.212?µM, competitive and reversible), AChE (IC50:0.264?µM, mixed and reversible) and BuChE (IC50:0.024?µM, mixed and reversible) inhibitor respectively. SAR studies disclosed several structural aspects significant for potency and selectivity and indicated the role of size of aryl binding site in potency and selectivity towards MAO-B. Antioxidant activity and neurotoxicity screening results further suggested their multifunctional potential for the therapy of neurodegenerative diseases. 相似文献
18.
Aamer Saeed Gufran Saddique Pervaiz Ali Channar Fayaz Ali Larik Qamar Abbas Mubashir Hassan Hussain Raza Tanzeela Abdul Fattah Sung-Yum Seo 《Bioorganic & medicinal chemistry》2018,26(12):3707-3715
To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (4a–4j) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives 4a–4j were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative 4a–4j showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound 4c exhibited higher potential in the series with IC50 0.251?±?0.012?µM (standard KH2PO4 4.317?±?0.201?µM). Lineweaver-Burk plots revealed that most potent derivative 4c inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds 4a–4j obey Lipinsk’s rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound 4c interacts with Asp273, His317 and Arg166 amino acid residues. 相似文献
19.
Mehdi Adib Fariba Peytam Reihaneh Shourgeshty Maryam Mohammadi-Khanaposhtani Mehdi Jahani Somaye Imanparast Mohammad Ali Faramarzi Bagher Larijani Ali Akbar Moghadamnia Ensieh Nasli Esfahani Fatemeh Bandarian Mohammad Mahdavi 《Bioorganic & medicinal chemistry letters》2019,29(5):713-718
Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC50?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC50 values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (Ki value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase. 相似文献
20.
Jiangtao Feng Haifeng He Yuan Zhou Meng Cai Hao Peng Honglin Liu Lei Liu Lingling Feng Hongwu He 《Bioorganic & medicinal chemistry》2019,27(24):115159
Harmful cyanobacteria bloom (HCB) has occurred frequently in recent years and it is urgent to develop novel algicides to deal with this problem. In this paper, a series of novel thiamin diphosphate (ThDP) analogs 5a?5g were designed and synthesized targeting cyanobacterial pyruvate dehydrogenase complex E1 (Cy-PDHc E1). Our results showed that compounds 5a?5g have higher inhibitory activities against Cy-PDHc E1 (IC50 9.56–3.48 µM) and higher inhibitory activities against two model cyanobacteria strains Synechocystis sp PCC6803 (EC50 2.03–1.58 µM) and Microcystis aeruginosa FACHB905 (EC50 1.86–0.95 µM). Especially, compound 5b displayed highest inhibitory activities (IC50 = 3.48 µM) against Cy-PDHc E1 and powerful inhibitory activities against cyanobacteria Synechocystis sp PCC6803 (EC50 = 1.58 µM) and Microcystis aeruginosa FACHB905 (EC50 = 1.04 µM). Moreover, the inhibitory activities of compound 5b were even higher than those of copper sulfate (EC50 = 2.02 and 1.71 µM separately) which has been widely used as algicide against cyanobacteria PCC6803 and FACHB905. The more important was that compound 5b display much higher inhibitory selectivity between Cy-PDHc E1 (Inhibitory rate 97.4%) and porcine PDHc E1 (Inhibitory rate 11.8%) under the same concentration (100 μM). The inhibition kinetic experiment and molecular docking research showed that compound 5b can inhibit Cy-PDHc E1 by occupying the ThDP-binding pocket and then blocking Cy-PDHc E1 bound to ThDP as competitive inhibitor. The imagines of SEM and TEM showed that cellular microstructures were heavily destroyed under compound 5b stress. Our results demonstrated compound 5b could be taken as a potential lead compound targeting Cy-PDHc E1 to obtain environment-friendly algicide for harmful cyanobacterial blooms control. 相似文献