Chromone-based benzohydrazide derivatives as potential α-glucosidase inhibitor: Synthesis, biological evaluation and molecular docking study.

In order to find new α-glucosidase inhibitors with high efficiency and low toxicity, novel chromone-based benzohydrazide derivatives 6a-6s were synthesized and characterized through 1H NMR, 13C NMR, and HRMS. All the new synthesized compounds were tested for inhibitory activities against α-glucosidase. Compounds 6a-6s with IC50 values ranging from 4.51 ± 0.09 to 27.21 ± 0.83 µM, showed a potential α-glucosidase inhibitory activity as compared to the positive control (acarbose: IC50 = 790.40 ± 0.91 µM). Compound 6i exhibited the highest α-glucosidase inhibitory activity with an IC50 value of 4.51 ± 0.09 µM. Theinteractionbetween α-glucosidase and 6i was further confirmed by enzyme kinetic, fluorescence quenching, circular dichroism, and molecular docking study. In vivo experiment showed that 6i could suppress the rise of blood glucose levels after sucrose loading. The cytotoxicity result indicated that 6i exhibited low cytotoxicity in vitro.

Design, synthesis, biological evaluation, and docking study of chromone-based phenylhydrazone and benzoylhydrazone derivatives as antidiabetic agents targeting α-glucosidase.

To develop novel α-glucosidase inhibitors, a series of chromone-based phenylhydrazone and benzoylhydrazone derivatives were designed, synthesized, and evaluated their inhibitory effects on α-glucosidase. The target compounds were characterized using 1H NMR, 13C NMR, and high-resolution mass spectra. Some of the compounds showed a varying degree of α-glucosidase inhibitory activity with IC50 values ranging from 6.59 ± 0.09 to 158.55 ± 0.87 µM. Among them, compound 5c (IC50 = 6.59 ± 0.09 µM) was the most potent inhibitor by comparison with positive control acarbose (IC50 = 685.11 ± 7.46 µM). Enzyme kinetic, fluorescence analysis, circular dichroism spectra, and molecular docking techniques were employed to explain the underlying molecular mechanisms of 5c inhibition on α-glucosidase. In vivo sucrose-loading test showed that 5c could suppress the rise of blood glucose levels after loading sucrose in normal Kunming mice. The cytotoxicity assay indicated that 5c exhibited low cytotoxicity.

Design, synthesis, biological evaluation, and docking study of new triazole-phenylacetamide derivatives as α-glucosidase inhibitors.

To discover potent α-glucosidase inhibitors, a class of novel triazole-phenylacetamide derivatives (5a-5p) were designed, prepared, and tested for their α-glucosidase inhibitory effects. All tested compounds (5a-5p) displayed a strong α-glucosidase inhibitory activity (IC50 = 6.69 ± 0.18-113.65 ± 2.94 µM) in comparison with the positive control acarbose (IC50 = 723.06 ± 11.26 µM). Thereinto, 5g (IC50 = 6.69 ± 0.18 µM) showed the best anti-α-glucosidase activity and behaved as a mixed-type inhibitor with the value of Ki and Kis to be 1.65 µM and 4.54 µM, respectively. Besides, fluorescence quenching experiment, three-dimensional fluorescence spectra assay, circular dichroism analysis, and molecular docking studies indicated that 5g may inhibit α-glucosidase activity by binding with its active site as well as changing the secondary structure of α-glucosidase. Combined with the inhibition effect on the rise of postprandial blood glucose level and low cytotoxicity of 5g, it could be concluded that these title compounds may play a role as lead compounds to develop novel α-glucosidase inhibitors.

An overview: metal-based inhibitors of urease.

Urease is a kind of nickel-dependent metalloenzyme, which exists in the biological world widely, and can catalyse the hydrolysis of urea into ammonia and carbon dioxide to provide a nitrogen source for organisms. Urease has important uses in agriculture and medicine because it can catalyse the production of ammonia. Therefore, in this review, metal-based inhibitors of urease will be summarised according to different transition metal ions. Including the urease inhibition, structure-activity relationship, and molecular docking. Importantly, among these reviewed effective urease inhibitors, most of copper metal complexes exhibited stronger urease inhibition with IC50 values ranging from 0.46 µM to 41.1 µM. Significantly, the collected comprehensive information looks forward to providing rational guidance and effective strategies for the development of novel, potent, and safe metal-based urease inhibitors, which are better for practical applications in the future.

A systematic review of synthetic tyrosinase inhibitors and their structure-activity relationship.

Tyrosinase is a copper-containing oxidation enzyme, which is responsible for the production of melanin. This enzyme is widely distributed in microorganisms, animals and plants, and plays an essential role in undesirable browning of fruits and vegetables, antibiotic resistance, skin pigment formation, sclerotization of cuticle, neurodegeneration, etc. Hence, it has been recognized as a therapeutic target for the development of antibrowning agents, antibacterial agents, skin-whitening agents, insecticides, and other therapeutic agents. With great potential application in food, agricultural, cosmetic and pharmaceutical industries, a large number of synthetic tyrosinase inhibitors have been widely reported in recent years. In this review, we systematically summarized the advances of synthetic tyrosinase inhibitors in the literatures, including their inhibitory activity, cytotoxicity, structure-activity relationship (SAR), inhibition kinetics, and interaction mechanisms with the enzyme. The collected information is expected to provide a rational guidance and effective strategy to develop novel, potent and safe tyrosinase inhibitors for better practical applications in the future.

A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors.

Microtubules play an important role in the process of cell mitosis and can form a spindle in the mitotic prophase of the cell, which can pull chromosomes to the ends of the cell and then divide into two daughter cells to complete the process of mitosis. Tubulin inhibitors suppress cell proliferation by inhibiting microtubule dynamics and disrupting microtubule homeostasis. Thereby inducing a cell cycle arrest at the G2/M phase and interfering with the mitotic process. It has been found that a variety of chalcone derivatives can bind to microtubule proteins and disrupt the dynamic balance of microtubules, inhibit the proliferation of tumour cells, and exert anti-tumour effects. Consequently, a great number of studies have been conducted on chalcone derivatives targeting microtubule proteins. In this review, synthetic or natural chalcone microtubule inhibitors in recent years are described, along with their structure-activity relationship (SAR) for anticancer activity.

Synthesis and antitumor activity of litseaone B analogues as tubulin polymerisation inhibitors.

A series of litseaone B analogues 4a∼4p were synthesised and antitumor activities of all compounds were screened. These compounds were designed by introducing different substituents on the B ring. Among these synthesised compounds, it was proved that 4k showed excellent activity against A549, HepG2, and HCT-15 cell lines, the IC50 values were 7.60 µM, 20.53 µM, and 4.59 µM, respectively. The results of tubulin polymerisation inhibition and immunofluorescence staining experiments displayed that 4k could act on tubulin and inhibit the polymerisation of tubulin. Moreover, the wound healing assay showed that 4k could inhibit the migration of A549 cells in a dose-dependent manner. Furthermore, the results of flow cytometry revealed that 4k was capable of blocking the cell cycle in the G2/M phase, inducing a decrease in the mitochondrial membrane potential and ultimately leading to apoptosis in A549 cells. Importantly, the possible binding model was also performed by molecular docking. Subject classification codes: short communication.

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors.

A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC50 values of 0.48 ± 0.03 and 0.97 ± 0.13 µM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC50 value of 3.3 µM, as compared to the standard drug colchicine (IC50 = 9.1 µM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.

Synthesis, biological evaluation and molecular docking investigation of new sulphonamide derivatives bearing naphthalene moiety as potent tubulin polymerisation inhibitors.

A new series of sulphonamide derivatives bearing naphthalene moiety were synthesised and evaluated for their antiproliferative and tubulin polymerisation inhibitory activities. These new compounds were evaluated for their in vitro antiproliferative activity against MCF-7 and A549 by using CCK-8 method. Among all the tested compounds, compound 5c with naphthalen-1-yl moiety exhibited the most potent antiproliferative activity against MCF-7 and A549 cell line, with IC50 values of 0.51 ± 0.03 µM and 0.33 ± 0.01 µM, respectively. The results of tubulin polymerisation assay shown that 5c exhibited a significant ability to inhibit tubulin polymerisation with IC50 value of 2.8 µM. Consistent with its antitubulin activity, 5c can significantly arrest the cell cycle at G2/M phase and induce apoptosis in MCF-7 cancer cells. Molecular docking study indicated that compound 5c inhibited tubulin polymerisation through interacting at the colchicine-binding site of tubulin. Furthermore, 5c exhibited low cytotoxic activity on human normal cell line.

Design, synthesis, biological evaluation and molecular docking studies of new chalcone derivatives containing diaryl ether moiety as potential anticancer agents and tubulin polymerization inhibitors.

A novel series of chalcone derivatives containing diaryl ether moiety (5a-5p) were designed, synthesized and evaluated their anti-tubulin polymerization activities and anticancer activities. Among them, compound 5b with 4-methoxy substitution on right aromatic ring was found to be most active on MCF-7, HepG2 and HCT116 cancer cell lines, with IC50 values of 3.44 ± 0.19, 4.64 ± 0.23, and 6.31 ± 0.27 µM, respectively. In vitro tubulin polymerization assay showed that 5b could effectively inhibit tubulin polymerization. Further mechanism studies revealed that 5b could induce G2/M phase arrest and cell apoptosis. Molecular docking studies revealed that 5b interact and bind at the colchicine binding site of the tubulin.

Design, synthesis, molecular modeling, and biological evaluation of pyrazole-naphthalene derivatives as potential anticancer agents on MCF-7 breast cancer cells by inhibiting tubulin polymerization.

A new series of pyrazole-naphthalene derivatives (5a-5q) have been synthesized and evaluated for their anticancer activity against human breast cancer cell lines (MCF-7). Most of newly synthesized compounds (except 5i, 5m, and 5p) exhibited potent antiproliferative activity in the range of IC50 = 2.78 ± 0.24 µM - 9.13 ± 0.47 µM. Among them, compound 5j (IC50 = 2.78 ± 0.24 µM), bearing ethoxy at the 4-position of the phenyl ring, was found to be the most active compound in this series of compounds, with five folds more active than the standard drug cisplatin (IC50 = 15.24 ± 1.27 µM). In addition, compound 5j and colchicine showed the same ability to inhibit tubulin polymerization with the IC50 values of 4.6 µM and 6.7 µM, respectively. Cellular mechanism studies elucidated that compound 5j arrested the cell cycle at G2/M phase and induced apoptosis. Furthermore, molecular docking analysis revealed that compound 5j formed stable interactions in the colchicine-binding site of tubulin.

Design, synthesis, and anticancer evaluation of benzophenone derivatives bearing naphthalene moiety as novel tubulin polymerization inhibitors.

A series of benzophenone derivatives bearing naphthalene moiety were designed, synthesized, characterized by 1H NMR, 13C NMR, and HRMS and evaluated for their antiproliferative activity against human breast cancer cell line (MCF-7). Most of the tested derivatives showed good to moderate cytotoxicity against MCF-7 cell line. Among them, compound 4u (IC50 = 1.47 ± 0.14 µM) was found to be the most active compound, which is more active than the standard drug cisplatin (IC50 = 15.24 ± 1.27 µM). In vitro tubulin polymerization inhibition assay, EBI competition assay, cell cycle analysis, and cell apoptosis assay identified that compound 4u was a new tubulin polymerization inhibitor by targeting the colchicine binding site. Besides, molecular docking study showed that compound 4u has high binding affinities with the colchicine binding site of tubulin through hydrogen bond, cation-π, and hydrophobic interaction.

Synthesis, biological evaluation, and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site.

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.

Design, Synthesis and Biological Evaluation of Novel 4-(4-Methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines as Tubulin Polymerization Inhibitors.

A novel series of 4-(4-methoxynaphthalen-1-yl)-5-arylpyrimidin-2-amines were designed, synthesized, and evaluated for their anticancer activities. Most of the synthesized compounds exhibited moderate to high antiproliferative activity in comparison to the standard drug cisplatin. Among them, 5i bearing ethoxy at the 4-position of the phenyl was found to be the most active on MCF-7 and HepG2 cancer cell lines, with IC50 values of 3.77 ± 0.36 and 3.83 ± 0.26 µM, respectively. Further mechanism study shown that 5i potently inhibited tubulin polymerization, induced cell cycle arrest at G2/M phase and cell apoptosis in MCF-7 cell line. Furthermore, molecular modeling study suggested that 5i probably binds to the colchicine site of tubulin.

Hybrid Network with Attention Mechanism for Detection and Location of Myocardial Infarction Based on 12-Lead Electrocardiogram Signals.

The electrocardiogram (ECG) is a non-invasive, inexpensive, and effective tool for myocardial infarction (MI) diagnosis. Conventional detection algorithms require solid domain expertise and rely heavily on handcrafted features. Although previous works have studied deep learning methods for extracting features, these methods still neglect the relationships between different leads and the temporal characteristics of ECG signals. To handle the issues, a novel multi-lead attention (MLA) mechanism integrated with convolutional neural network (CNN) and bidirectional gated recurrent unit (BiGRU) framework (MLA-CNN-BiGRU) is therefore proposed to detect and locate MI via 12-lead ECG records. Specifically, the MLA mechanism automatically measures and assigns the weights to different leads according to their contribution. The two-dimensional CNN module exploits the interrelated characteristics between leads and extracts discriminative spatial features. Moreover, the BiGRU module extracts essential temporal features inside each lead. The spatial and temporal features from these two modules are fused together as global features for classification. In experiments, MI location and detection were performed under both intra-patient scheme and inter-patient scheme to test the robustness of the proposed framework. Experimental results indicate that our intelligent framework achieved satisfactory performance and demonstrated vital clinical significance.

Synthesis, Anticancer Activity and Molecular Modeling Studies of Novel Chalcone Derivatives Containing Indole and Naphthalene Moieties as Tubulin Polymerization Inhibitors.

Eighteen novel chalcone derivatives containing indole and naphthalene moieties (2-19) were synthesized and characterized by 1H-NMR, 13C-NMR and high resolution (HR)-MS spectra. All compounds were evaluated for their in vitro cytotoxic potential against human hepatocellular carcinoma (HepG2), human colon carcinoma (HCT116) and human breast adenocarcinoma (MCF-7) cell lines. Among them, compound 2, 3, 4 and 7 showed potent activities against tested cancer cell lines. More significantly, compound 7 exhibited the most potent cytotoxic activity against HepG2, HCT116 and MCF-7 with IC50 values of 0.65, 1.13 and 0.82 µM, respectively. Furthermore, flow cytometry analysis indicated that compound 7 arrested cancer cells in G2/M phase. The compound 7 also displayed significant inhibition of tubulin polymerization (IC50 = 3.9 µM). Finally, molecular docking studies were performed to explore the possible interactions between compound 7 and tubulin binding pockets.

A Novel Framework with High Diagnostic Sensitivity for Lung Cancer Detection by Electronic Nose.

The electronic nose (e-nose) system is a newly developing detection technology for its advantages of non-invasiveness, simple operation, and low cost. However, lung cancer screening through e-nose requires effective pattern recognition frameworks. Existing frameworks rely heavily on hand-crafted features and have relatively low diagnostic sensitivity. To handle these problems, gated recurrent unit based autoencoder (GRU-AE) is adopted to automatically extract features from temporal and high-dimensional e-nose data. Moreover, we propose a novel margin and sensitivity based ordering ensemble pruning (MSEP) model for effective classification. The proposed heuristic model aims to reduce missed diagnosis rate of lung cancer patients while maintaining a high rate of overall identification. In the experiments, five state-of-the-art classification models and two popular dimensionality reduction methods were involved for comparison to demonstrate the validity of the proposed GRU-AE-MSEP framework, through 214 collected breath samples measured by e-nose. Experimental results indicated that the proposed intelligent framework achieved high sensitivity of 94.22%, accuracy of 93.55%, and specificity of 92.80%, thereby providing a new practical means for wide disease screening by e-nose in medical scenarios.

(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design, synthesis, biological evaluation, molecular docking and in silico ADME prediction.

A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC50 value of 0.26-0.61 µM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC50 values in the range of 0.077- 7.44 µM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC50 value of 0.9 µM, with ten folds more active than colchicine (IC50 = 9 µM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.

Synthesis, biological evaluation, and docking studies of novel 5,6-diaryl-1,2,4-triazine thiazole derivatives as a new class of α-glucosidase inhibitors.

A novel 5,6-diaryl-1,2,4-triazine thiazole derivatives (7a-7q) were synthesized and characterized by 1H NMR and 13C NMR and evaluated for their α-glucosidase inhibitory activity. All tested compounds displayed good α-glucosidase inhibitory activity with IC50 values ranging between 2.85 ±â€¯0.13 and 14.19 ±â€¯0.23 µM when compared to the standard drug acarbose (IC50 = 817.38 ±â€¯6.27 µM). Compound 7i (IC50 = 2.85 ±â€¯0.13 µM) exhibited the highest activity among this series of compounds. Molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to α-glucosidase. This study showed that these 5,6-diaryl-1,2,4-triazine thiazole derivatives are a new class of α-glucosidase inhibitors.

Synthesis, biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site.

A series of aminochalcone derivatives have been synthesized, characterized by HRMS, 1H NMR and 13C NMR and evaluated for their antiproliferative activity against HepG2 and HCT116 human cancer cell lines. The most of new synthesized compounds displayed moderate to potent antiproliferative activity against test cancer cell lines. Among the derivatives, compound 4 displayed potent inhibitory activity with IC50 values ranged from 0.018 to 5.33 µM against all tested cancer cell lines including drug resistant HCT-8/T. Furthermore, this compound showed low cytotoxicity on normal human cell lines (LO2). The in vitro tubulin polymerization assay showed that compound 4 inhibited tubulin assembly in a concentration-dependent manner with IC50 value of 7.1 µM, when compared to standard colchicine (IC50 = 9.0 µM). Further biological evaluations revealed that compound 4 was able to arrest the cell cycle in G2/M phase. Molecular docking study demonstrated the interaction of compound 4 at the colchicine binding site of tubulin. All the results indicated that compound 4 is a promising inhibitor of tubulin polymerization for the treatment of cancer.