- Synthesis and Biological Evaluation of Dithiobisacetamides as Novel Urease Inhibitors
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Thirty-eight disulfides containing N-arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds exhibited strong inhibitory potency against both cell-free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′-dithiobis(N-(2-fluorophenyl)acetamide) (d7), 2,2′-dithiobis(N-(3,5-difluorophenyl)acetamide) (d24), and 2,2′-dithiobis(N-(3-fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32- to 355-fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti-Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections.
- Liu, Mei-Ling,Li, Wei-Yi,Fang, Hai-Lian,Ye, Ya-Xi,Li, Su-Ya,Song, Wan-Qing,Xiao, Zhu-Ping,Ouyang, Hui,Zhu, Hai-Liang
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- COMBINATION THERAPY FOR TREATING MPS1
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The application is directed to compounds of formula (I) and their salts and solvates, wherein B, R1, R2, R3, R3', R4, R4', and R5 are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., MPS1, optionally in combination with α-L-iduronidase or an analog or variant thereof, e.g., laronidase.
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Paragraph 0464-0465; 0466-0468; 0480-0482
(2021/08/14)
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- Design, synthesis, antibacterial and quorum quenching studies of 1,2,5-trisubstituted 1,2,4-triazoles
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Abstract: In view of discovering novel bioactive molecules, 1-phenyl-1H-2-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)-3-(N-aryl-carbamoylmethylthio)-1,2,4-triazoles (8a–n) were designed and synthesized in good yield. Preliminary antibacterial activity was tested against Chromobacterium violaceum and Xanthomonas campestris pv. Campestris (Xcc). Out of 14 derivatives, compound 8g selectively possessed antibacterial activity against C. violaceum. Further derivatives that possessed an electron-withdrawing group and halogen atoms in N-phenylacetamide moiety were moderately active against Xcc (plant pathogen). After observing the reduction of violacein production through plate assay, compounds 8a, 8c, 8h, 8i and 8m were subjected to quantification of quorum sensing inhibition. Compounds with the electron-withdrawing group in N-phenylacetamide moiety showed admirable activity with > 80% inhibition of violacein. Mainly compound 8c which was inactive against the growth of bacteria were identified as excellent QSI which could be a lead compound for further development. Graphic abstract: One of the best approaches to acquire anti-virulence strategies and new direction for the discovery of antibacterial drugs[Figure not available: see fulltext.]
- Sathyanarayana, Reshma,Bajire, Sukesh Kumar,Poojary, Boja,Shastry, Rajesh P.,Kumar, Vasantha,Chandrashekarappa, Revanasiddappa Bistuvalli
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p. 1051 - 1066
(2020/10/22)
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- Design, synthesis and biological evaluation of novel 5-(4-chlorophenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols as an anticancer agent
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Cellular tumor antigen p53 is significant for cancer prevention and its mutation is most documented genomic change in human cancers. Thus, restoration of p53 function by interruption of the p53-MDM2 interaction opens up a prospect for a nongenotoxic anticancer therapeutic strategy. A novel series of molecules comprising 1,2,4-triazole-3-thiol scaffold were successfully discovered by structure-based designing approach. In silico modules predicted that 5-(4-chlorophenyl)-4-phenyl-4H-1,2,4-triazole-3-thiol derivatives have draggability and ability to mimic critical binding residues of p53. All target compounds were assayed for their in vitro antiproliferative activity against A549, U87 and HL60 cell lines. Twelve out of sixteen compounds exhibited good in vitro inhibitory activity in micromolar range. Especially, compound 6h possessed acute antitumor activity with IC50 values 3.854, 4.151 and 17.522 μM against three tested cell lines. It represents as a promising lead for further optimization and a template for development of novel antitumor agents.
- Patel, Krupa R.,Brahmbhatt, Jpan G.,Pandya, Pranav A.,Daraji, Drashti G.,Patel, Hitesh D.,Rawal, Rakesh M.,Baran, Sujit K.
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- Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection
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Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aβ deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aβ1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
- Li, Qi,Chen, Ying,Xing, Shuaishuai,Liao, Qinghong,Xiong, Baichen,Wang, Yuanyuan,Lu, Weixuan,He, Siyu,Feng, Feng,Liu, Wenyuan,Chen, Yao,Sun, Haopeng
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p. 6856 - 6876
(2021/05/29)
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- Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
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In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.
- Chao, Gao,Dai, Honglin,Ke, Yu,Li, Erdong,Lihong, Shan,Liu, Hongmin,Liu, Limin,Si, Xiaojie,Wang, Zhengjie,Yang, Zhang,Zhang, Luye,Zhang, Qiurong,Zheng, Jiaxin
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- Synthesis of New Thieno[2,3-d]pyrimidines Containing a 1,2,3-Triazole Ring and Their Therapeutic Response in NCI-60 Cell Line Panel
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Abstract: A series of new tetrahydro[1]benzothieno[2,3-d]pyrimidines containing a 1,2,3-triazole fragment linkedthrough an oxymethylene spacer have been synthesized by click reaction of4-(prop-2-yn-1-yloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines with various aryl and alkyl azides inthe presence of copper sulfate and sodium ascorbate as a catalyst. Thestructures of the synthesized compounds were characterized by variousspectroscopic techniques (1H and13C NMR, FT-IR, and mass spectrometry), and theirin vitro anticancer activity against NCI-60 human tumor cell lines wasevaluated. Among the compounds tested, N-(pyridine-3-yl)-acetamide derivative exhibited significantactivity against several cancer cell lines, including SF-539 (CNS cancer),HCT-116 (colon cancer), OVCAR-8 (ovarian cancer), PC-3 (prostate cancer), andCCRF-CEM (leukemia).
- Baluja, S. H.,Bhensdadia, K. A.,Lalavani, N. H.
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p. 1668 - 1677
(2021/12/13)
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- Antidiabetic compounds
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Compounds for the treatment of hyperglycemia and/or diabetes are provided. The compounds, which inhibit the enzyme dipeptidyl peptidase (DPP-4), are based on the structure where X may be present or absent an may be OH, Ar is an aryl group; and n ranges from 0 to 5.
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Page/Page column 13-14
(2020/06/16)
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- Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
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In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
- Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
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- Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives
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With the surge in the cases of Alzheimer's disease (AD) over the years, several targets have been explored to curb the disease. Cholinesterases, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), remain to be the available targets that are amendable to currently approved treatments. In this study, a series of novel compounds based on tramiprosate, a highly specific amyloid beta (Aβ) inhibitor, was designed to inhibit AChE, BuChE, and Aβ aggregation. In particular, the addition of a pyridinium/isoquinolinium ring to the tramiprosate moiety (to give compounds 3a–j) led to an increase in the binding affinity for the catalytic active site of cholinesterase, which was hampered by the presence of sulfonic acid. Exclusion of the sulfonic acid moiety led to a novel but effective class of cholinesterase inhibitors (9a–w). in vitro Aβ aggregation inhibition assay indicated that compounds 3a–j, 9e–f, 9i–l, 9q, 9r, 9u–w, and 12 could inhibit over 10% Aβ aggregation at 1 mM concentration. Cholinesterase inhibition assay suggested that compounds 9g, 9h, 9o, and 9q–t exhibit over 70% inhibition on both AChE and BuChE at a concentration of 100 μM. Amongst the designed molecules, compound 9r (ca 18% at 1 mM) showed comparable inhibitory effect on the inhibition of Aβ aggregation with tramiprosate (ca 20% at 1 mM), along with impressive cholinesterase inhibitory potential (AChE IC50 = 13 μM and BuChE IC50 = 12 μM), acceptable toxicity and ability to pass through blood brain barrier, which could be used to ameliorate the phenotypes of AD in preclinical models.
- Chakravarty, Harapriya,Ju, Yaojun,Chen, Wen-Hua,Tam, Kin Y.
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p. 242 - 255
(2019/12/27)
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- Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation
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Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
- Aguilera, Renato J.,Choe, Jun-yong,Henze Macias, Luca,Hess, Jessica D.,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,J?nsch, Niklas
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- Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential
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Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital ro
- Aguilera, Renato J.,Choe, Jun-yong,Hess, Jessica D.,Iancu, Cristina V.,Macias, Lucasantiago Henze,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Tilekar, Kalpana,Upadhyay, Neha
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- Design, Synthesis, and Bioactivity of α-Ketoamide Derivatives Bearing a Vanillin Skeleton for Crop Diseases
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A series of novel α-ketoamide derivatives bearing a vanillin skeleton were designed and synthesized. Bioactivity tests on virus and bacteria were performed. The results indicated that some compounds exhibited excellent antitobacco mosaic virus (TMV) activities, such as compound 34 exhibited an inactivation activity of 90.1percent and curative activity of 51.8percent and compound 28 exhibited a curative activity of 54.8percent at 500 μg mL-1, which is equivalent to that of the commercial ningnanmycin (inactivation of 91.9percent and curative of 51.9percent). Moreover, the in vitro antibacterial activity test illustrated that compounds 2, 22, and 33 showed much higher activities than commercial thiodiazole copper, which could be used as lead compounds or potential candidates. The findings of transmission electron microscopy and molecular docking indicated that the synthesized compounds exhibited strong and significant binding affinity to the TMV coat protein and could obstruct the self-assembly and increment of TMV particles. This study revealed that α-ketoamide derivatives bearing a vanillin skeleton could be used as a novel potential pesticide for controlling the plant diseases.
- Chen, Shunhong,Dai, Ali,Guo, Shengxin,He, Feng,Luo, Dexia,Wu, Jian,Zhang, Renfeng
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p. 7226 - 7234
(2020/08/06)
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- Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
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Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
- Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
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- Ultrasonic-Assisted Synthesis of Pyrazolo[3,4-d]pyrimidin-4-ol Tethered with 1,2,3-Triazoles and Their Anticancer Activity
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Abstract: In the presents work synthesis and characterization of new heterocyclic derivatives containing pyrazolo[3,4-d]pyrimidine linkage with 1,4-disubstituted-1,2,3-triazoles via methylene-oxy group. The selected synthesized compounds were tested for their in-vitro anticancer activity against various cancer cell lines. Synthesis of compounds was done under ultrasonic-assisted Huisgen 1,3-dipolar cycloaddition reaction with good yields. Some of the newly synthesized compounds demonstrated good to moderate anticancer activity, most of compounds shows activity against renal cancer cell lines.
- Bhatt, Tejal D.,Gojiya, Dinesh G.,Hadiyal, Sanjay D.,Joshi, Dr. Hitendra S.,Kapupara, Vimal H.,Prakash, L. Kalavadiya
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p. 803 - 813
(2020/10/29)
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- Design and synthesis of C-19 isosteviol derivatives as potent and highly selective antiproliferative agents
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Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. M
- Luan, Tian,Cao, Li-Hua,Deng, Hao,Shen, Qing-Kun,Tian, Yu-Shun,Quan, Zhe-Shan
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- Halogen-substituted triazolethioacetamides as a potent skeleton for the development of metallo-β-lactamase inhibitors
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Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032–15.64 μM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 μM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 μM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.
- Zhang, Yilin,Yan, Yong,Liang, Lufan,Jiefeng,Wang, Xuejun,Li, Li,Yang, Kewu
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- Ether acetamide derivative containing alpha-carbonyl amide structure and application of ether acetamide derivative
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The invention discloses application of an ether acetamide derivative containing an alpha-carbonyl amide structure in an aspect of resisting plant diseases. The structure is shown in a general formulaI. Limitation of groups such as R and R is shown as the specification. A compound shown in the general formula I has a function of preventing and treating the plant diseases, and TMV, rice bacterial blight, citrus canker, ralstonia solanacearum and other plant virus diseases can be prevented and treated.
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Paragraph 0045; 0047
(2019/11/12)
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- A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions
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The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.
- Tabatabaei Dakhili, Seyed Amirhossein,Pérez, David J.,Gopal, Keshav,Tabatabaei Dakhili, Seyed Yasin,Ussher, John R.,Velázquez-Martínez, Carlos A.
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supporting information
(2019/10/28)
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- Synthesis, antiproliferative evaluation, and structure–activity relationships of novel triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety
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As an aspect of our ongoing research on developing novel antiproliferative agents, 31 new triazole–isoindoline hybrids bearing 3,4,5-trimethoxyphenyl moiety were synthesized and evaluated for their antiproliferative activity against four cancer cell lines (HepG2, HeLa, PC-3, and HCT116). Some compounds showed excellent potency, and compared to fluorouracil, the most promising compound 6s exhibited 5.8-, 4.3-, and 1.3- fold increase in activities against HeLa, HepG2, and PC-3 cell lines with IC50 values of 9.7, 10.7, and 16.8?μM, respectively. Moreover, structure–activity relationship studies indicated that a much shorter amide linkage and electron-withdrawing groups at phenyl ring of the acetamide fragment contribute to the antitumour activity.
- Li, Qiu,Chen, Peng,Yang, Haikui,Luo, Miaolan,You, Wenwei,Zhao, Peiliang
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p. 651 - 659
(2018/02/28)
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- An efficient, four-component reaction for the synthesis of novel carbamodithioates
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A series of substituted phenylcarbamoyl methyl benzylcarbamodithioates have been synthesized using the multicomponent condition. The reaction proceeded under mild practical condition and afforded the desired products in good yields.
- Sadat-Ebrahimi, Seyed Esmail,Karim, Leila,Moghimi, Setareh,Yahya-Meymandi, Azadeh,Mahdavi, Mohammad,Vosooghi, Mohsen,Foroumadi, Alireza,Shafiee, Abbas
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- Design, synthesis and biological evaluation of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives
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Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50values of 0.37, 2.94, and 31.31 μM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.
- Zhao, Pei-Liang,Chen, Peng,Li, Qiu,Hu, Meng-Jin,Diao, Peng-Cheng,Pan, En-Shan,You, Wen-Wei
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p. 3679 - 3683
(2016/07/21)
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- Synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives incorporating benzisoselenazolone scaffold as potential antitumor agents
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Background: Based on the biological signi-cance of benzisoselenazolone and 1,3,4-thiadiazole, a series of novel 1,3,4-thiadiazole derivatives incorporating benzisoselenazolone scaffold were designed and synthesized with ebselen as a lead compound. Methods: Meanwhile, their in vitro antitumor activities were evaluated against SMMC-7721, MCF-7 and A549 human cancer cell lines by CCK-8 assay. Results: The preliminary bioassay results demonstrated that all tested compounds 4a-q showed potent antitumor activities, and some compounds exhibited better effects than positive control ethaselen and 5-fluorouracil (5-FU) against various cancer cell lines. Furthermore, compounds 4b and 4m showed significant antitumor activities against SMMC-7721 cells with IC50 values of 1.89 and 1.89 μM, respectively. Compounds 4c and 4n displayed highly effective biological activities against MCF-7 cells with IC50 values of 2.88 and 2.28 μM, respectively. Compound 4i showed the best inhibitory effect against A549 cells with IC50 value of 1.76 μM. Conclusion: The pharmacological results suggest that the substituent groups of phenyl ring on the 1,3,4-thiadiazole are vital for modulating antitumor activities against various cancer cell lines.
- Fu, Xiaoyun,Li, Sha,Jing, Fen,Wang, Xuefeng,Li, Baolin,Zhao, Jijun,Liu, Yuming,Chen, Baoquan
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p. 631 - 639
(2016/10/18)
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- Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies
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Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED50 = 23.5 mg/kg, MES, mice, i.p.; ED50 = 32.6 mg/kg, scPTZ, mice, i.p.; ED50 = 45.2 mg/kg, 6-Hz, mice, i.p.; TD50 = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED50 = 26.1 mg/kg, MES, mice, i.p.; ED50 = 79.4 mg/kg, scPTZ, mice, i.p.; TD50 = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.
- Ugale, Vinod G.,Bari, Sanjay B.
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p. 864 - 880
(2016/11/09)
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- Discovery of novel AHLs as potent antiproliferative agents
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Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.
- Ren, Jing-Li,Zhang, Xu-Yao,Yu, Bin,Wang, Xi-Xin,Shao, Kun-Peng,Zhu, Xiao-Ge,Liu, Hong-Min
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p. 321 - 329
(2015/03/04)
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- Chloroquinoline-acetamide hybrids: A promising series of potential antiprotozoal agents
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In an endeavour to develop efficacious antiprotozoal agents 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]acetamide derivatives were synthesized and screened in vitro against the HM1:IMSS strain of E. histolytica and 3D7 strain of P. falciparum. Among the twenty-seven synthesized compounds, eleven evinced propitious anti-amoebic activity with IC50 values ranging from 0.41 to 1.80 μM) lower than the standard drug metronidazole (IC50 1.80 μM). All the compounds inhibited the in vitro growth of P. falciparum (IC50 range: 0.30-33.52 μM). Compounds A22 and A25 were found to be the most active antimalarial derivatives, and compound A16 the most active in inhibiting β-haematin formation; however compound A25 displayed the more favourable safety profile. The crystal structure for the compounds A7, A8, A12 and A21 was also determined. The molecular docking of crystal resolved inhibitors with PfDHFR allowed identification of stabilizing interactions within enzyme active sites. These compounds affirm the potential for further derivatives to enhance antiprotozoal activity whilst retaining their safety profile.
- Inam, Afreen,Van Zyl, Robyn L.,Van Vuuren, Natasha J.,Chen, Chien-Teng,Avecilla, Fernando,Agarwal, Subhash M.,Azam, Amir
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p. 48368 - 48381
(2015/06/16)
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- Design, Synthesis, and Biological Evaluation of Chalcone Derivatives as Novel Anticandidal Agents
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Twenty chalcone derivatives were designed and synthesized with a view to developing novel anticandidal agents. All the compounds were evaluated for their antifungal activity against Candida albicans (ATCC 10231 and ten clinical isolates). Most of them exhibited moderate anticandidal potency with MIC values ranging from 2.0 to 32.0 μg/mL. Four compounds (T4, T6, T19, T20) displayed potent anticandidal activity with MIC values of 2.0 μg/mL. Compound T6 showed the most potent activity against Candida albicans (ATCC 10231 and four clinical isolates). In addition, attempts have also been made to correlate anticandidal activity to physicochemical properties. The results indicated that incorporation of halogen on the benzene ring is beneficial for anticandidal activity.
- Shan, Yuanyuan,Lei, Jine,Zhang, Li,Fan, Te,Wang, Maoyi,Ma, Ying
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p. 620 - 625
(2015/08/24)
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- Development of Small-Molecule Cryptochrome Stabilizer Derivatives as Modulators of the Circadian Clock
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Small-molecule probes have been playing prominent roles in furthering our understanding of the molecular underpinnings of the circadian clock. We previously discovered a carbazole derivative, KL001 (N-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-N-(furan-2-ylme
- Lee, Jae Wook,Hirota, Tsuyoshi,Kumar, Anupriya,Kim, Nam-Jung,Irle, Stephan,Kay, Steve A.
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supporting information
p. 1489 - 1497
(2015/09/07)
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- 6-bromo-2,3-dioxoindolin phenylacetamide derivatives: Synthesis, potent CDC25B, PTP1B inhibitors and anticancer activity
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A series of 6-bromo-2,3-dioxoindolin phenylacetamide derivatives was synthesized and evaluated for inhibitory activity against CDC25B and PTP1B. Most of the synthesized compounds showed potential inhibitory activities for CDC25B and PTP1B with compound 12 being the most potent (IC50=3.87μmol/L and 2.98 μmol/L, respectively). Compound 12 also exhibited higher cytotoxic activity against three cancer cell lines (HeLa, A549 and HCT116). In addition, compound 12 delayed the potent tumor inhibitory activity in a colo205 xenograft model in vivo.
- Zhao, Shui-Lian,Peng, Zhou,Zhen, Xing-Hua,Han, Yan,Jiang, Hai-Ying,Qu, You-Le,Guan, Li-Ping
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p. 529 - 536
(2016/03/22)
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- Synthesis, cytotoxic study and docking based multidrug resistance modulator potential analysis of 2-(9-oxoacridin-10(9H)-yl)-N-phenyl acetamides
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The present study describes the synthesis of fifteen 2-(9-oxoacridin-10(9H) -yl)-N-phenyl acetamide derivatives (13a-o) through condensation of 2-chloro-N-phenyl acetamides (12a-o) with acridone molecule (10). All the synthesized compounds were screened f
- Kumar, Rajesh,Kaur, Maninder,Bahia, Malkeet Singh,Silakari, Om
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- Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a] phthalazine derivatives
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Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 μM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.
- Xue, Deng-Qi,Zhang, Xu-Yao,Wang, Chao-Jie,Ma, Li-Ying,Zhu, Nan,He, Peng,Shao, Kun-Peng,Chen, Peng-Ju,Gu, Yi-Fei,Zhang, Xiao-Song,Wang, Cai-Feng,Ji, Cong-Hui,Zhang, Qiu-Rong,Liu, Hong-Min
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p. 235 - 244
(2014/08/18)
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- Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential glycosyltransferase inhibitors
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Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure-based virtual screening of about 3 000 000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin-binding protein 2 (S. aureus PBP2) resulted in identification of an isatin derivative, 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(m-tolyl)acetamide (4) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4, in particular 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(3-nitrophenyl)acetamide (4l), against Gram-positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 lg/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD-NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.
- Wang, Yong,Chan, Fung-Yi,Sun, Ning,Lui, Hok-Kiu,So, Pui-Kin,Yan, Siu-Cheong,Chan, Kin-Fai,Chiou, Jiachi,Chen, Sheng,Abagyan, Ruben,Leung, Yun-Chung,Wong, Kwok-Yin
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p. 685 - 696
(2015/01/09)
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- Design, synthesis and antibacterial evaluation of novel AHL analogues
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Two series of novel AHL analogues were designed, synthesized and evaluated for antibacterial activity under cell membrane conditions in vitro. Analogues 4a-c and 4g-m presented potent activity against Gram-positive bacteria. Especially the analogue 4l exe
- Ren, Jing-Li,Zhang, En,Ye, Xian-Wei,Wang, Meng-Meng,Yu, Bin,Wang, Wen-Hua,Guo, Ya-Zhuo,Liu, Hong-Min
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supporting information
p. 4154 - 4156
(2013/07/25)
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- Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors
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Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization.
- Wang, Fang,Lu, Wen,Zhang, Tao,Dong, Jinyun,Gao, Hongping,Li, Pengfei,Wang, Sicen,Zhang, Jie
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p. 6973 - 6980
(2013/11/06)
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- Arylazolylthioacetanilide. Part 11: Design, synthesis and biological evaluation of 1,2,4-triazole thioacetanilide derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
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A series of novel 1,2,4-triazole thioacetanilide derivatives has been designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. Half of these compounds showed moderate to potent activities against wild-type HIV-1 with an EC50 ranging from 38.0 μM to 4.08 μM. Among them, 2-(4-(2-fluorobenzyl)-5-isopropyl-4H-1,2,4-triazol-3-ylthio)-N-(2-nitrophenyl) acetamide 7d was identified as the most promising compound (EC50 = 4.26 μM, SI = 49). However, no compound was active against HIV-2. The preliminary structure-activity relationships among the newly synthesized congeners are discussed.
- Li, Zhenyu,Cao, Yuan,Zhan, Peng,Pannecouque, Christophe,Balzarini, Jan,De Clercq, Erik,Shen, Yuemao,Liu, Xinyong
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p. 968 - 973
(2014/01/06)
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- Synthesis and biological evaluation of 1,4-diazepane derivatives as T-type calcium channel blockers
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We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.
- Gu, Su Jin,Lee, Jae Kyun,Pae, Ae Nim,Chung, Hye Jin,Rhim, Hyewon,Han, So Yeob,Min, Sun-Joon,Cho, Yong Seo
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scheme or table
p. 2705 - 2708
(2010/07/15)
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- Synthesis and antitumor activities of novel 1,4-substituted phthalazine derivatives
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A series of 1,4-substituted phthalazine derivatives were designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, HT-29 and MDA-MB-231 cell lines in vitro. Among them, compounds 7a-7h showed excellent selectivity for MDA-MB-231 cell line with IC50 values from 1nmol/L to 0.92μmol/L. A preliminary SAR study of these derivatives was performed.
- Zhang, Shu Lan,Liu, Ya Jing,Zhao, Yan Fang,Guo, Qiu Ting,Gong, Ping
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scheme or table
p. 1071 - 1074
(2011/10/05)
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- Evaluation of glycolamide esters of indomethacin as potential cyclooxygenase-2 (COX-2) inhibitors
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A number of novel indomethacin glycolamide esters were synthesized and tested for their cyclooxygenase (COX-1 and COX-2) inhibition properties in vitro. Many of these compounds proved to be selective COX-2 inhibitors, and subtle structural changes in the substituents on the glycolamide ester moiety altered the inhibitory properties as well as potencies significantly. Their in vitro data were rationalized through molecular modeling studies. Few of them displayed anti-inflammatory activity in vivo. Compound 32, [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid 2-morpholin-4-yl-2-oxo ethyl ester, was identified as a promising compound in this class and its good anti-inflammatory activity was demonstrated in the in vivo model.
- Khanna, Smriti,Madan, Manjula,Vangoori, Akhila,Banerjee, Rahul,Thaimattam, Ram,Jafar Sadik Basha,Ramesh, Mullangi,Casturi, Seshagiri Rao,Pal, Manojit
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p. 4820 - 4833
(2007/10/03)
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS
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Disclosed are novel heterocyclic derivatives, useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.
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- Synthesis and functional activity of (2-aryl-1-piperazinyl)-N-(3- methylphenyl)acetamides: Selective dopamine D4 receptor agonists
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Diaryl piperazine acetamides were identified as potent and selective dopamine D4 receptor agonists. Our strategy is based on an amide bond reversal of an acid sensitive, dopamine D4 receptor partial agonist, PD 168077. This reversal provided compounds with excellent potency and improved stability. Systematic evaluation of the substitution on the aryl piperazine portion revealed a significant effect on functional activity. The synthesis and biological activity of these new dopamine D4 agonists is discussed.
- Matulenko, Mark A.,Hakeem, Ahmed A.,Kolasa, Teodozyi,Nakane, Masaki,Terranova, Marc A.,Uchic, Marie E.,Miller, Loan N.,Chang, Renjie,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Moreland, Robert B.,Brioni, Jorge D.,Stewart, Andrew O.
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p. 3471 - 3483
(2007/10/03)
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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- Activities of 2-carboxanilido 3-hydroxybenzo[b]thiophens against molluscs Biomphalaria
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The title compounds are shown to be nearly as active against molluscs as Niclosamide when they are either dihalogenated or monohalogenated and mononitrated on the benzene ring.
- Gayral,Buisson,Royer
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p. 187 - 189
(2007/10/02)
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