- Design and synthesis of 3-substituted indolin-2-one derivatives with methyl (e)-2-(3-Methoxy) acrylate moiety
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In this article, fifteen indolin-2-one derivatives with methyl (E)-2-(3-methoxy)acrylate group were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, IR and HR-MS spectra analysis.
- Luo, Xi,Zhang, Yi-Ying,Wang, Yu-Liang
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- Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line
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Isatin is a versatile compound with a diversity of effects. We designed to investigate the inhibitory effect of isatin derivatives on lipopolysaccharide/interferon-γ-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, production of prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor (TNF-α), and their capacity to scavenge NO. Isatins inhibit TNF-α production and iNOS and COX-2 protein expression resulting on reduced levels of NO and PGE2. Our results indicate isatin and it derivatives as inhibitors of iNOS and COX-2 enzymes, which might be used as anti-inflammatory and antitumoral agents.
- Matheus, Maria Eline,Violante, Flavio de Almeida,Garden, Simon John,Pinto, Angelo C.,Fernandes, Patricia Dias
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- The mechanism of Sandmeyer's cyclization reaction by electrospray ionization mass spectrometry
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Using electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)) spectrometric experiments, the Sandmeyer reaction was monitored on-line, and key intermediates were intercepted and characterized for the first time. The mechanistic information provided by on-line ESI-MS(/MS) is in accordance with Sandmeyer's proposal, and was made possible by coupling a microreactor on-line to the ESI ion source, which allowed reactions to be screened from 0.7-2.0 s, identifying and characterizing all intermediates that were formed and consumed during the reaction. Copyright
- Silva, Barbara V.,Violante, Flavio A.,Pinto, Angelo C.,Santos, Leonardo S.
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- Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl)isatin derivatives as anticancer agents
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Forty four di- or trisubstituted novel isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of these new isatin derivatives against three human tumor cell lines, K562, HepG2 and HT-29, were evaluated by MTT assay in vitro. SAR studies suggested that the combination of 1-benzyl and 5-[trans-2- (methoxycarbonyl)ethen-1-yl] substitution greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 as present in the parent ring is required to such a potency. This study leads to the identification of two highly active molecules, compounds 2h (IC50 = 3 nM) and 2k (IC50 = 6 nM), against human leukemia K562 cells.
- Han, Kailin,Zhou, Yao,Liu, Fengxi,Guo, Qiannan,Wang, Pengfei,Yang, Yao,Song, Binbin,Liu, Wei,Yao, Qingwei,Teng, Yuou,Yu, Peng
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- Microwave assisted preparation of isatins and synthesis of (±)- convolutamydine-A
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Microwave assisted preparation of a number of isatin derivatives is reported. A simple synthesis of (±)-convolutamydine-A, a potent compound against leukemia cells, is presented.
- Jnaneshwara,Bedekar,Deshpande
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- Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors
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Histone deacetylases (HDACs) are zinc-dependent or NAD+ dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds synthesized have exhibited moderate Hela cell nuclear extract inhibitory activities, among which compound 25a (IC50 = 10.13 nM) has shown the best efficacy. The anti-proliferative activities of some of these compounds were also discussed.
- Jin, Kang,Li, Shanshan,Li, Xiaoguang,Zhang, Jian,Xu, Wenfang,Li, Xuechen
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- A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: Construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters
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A cinchona alkaloid catalyzed diastereoselective and enantioselective sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and isoindigos has been successfully developed to afford the highly congested bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters in high yields (up to 91%), excellent diastereoselectivities (up to >20 : 1 dr), and good enantioselectivities (up to 98% ee). Some synthetic transformations of the reaction products were also studied.
- Gui, Yong-Yuan,Yang, Jian,Qi, Liang-Wen,Wang, Xiao,Tian, Fang,Li, Xiao-Nian,Peng, Lin,Wang, Li-Xin
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- A modified Sandmeyer methodology and the synthesis of (±)-convolutamydine A
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(±)-Convolutamydine A (5) has been prepared by it concise synthesis from 3,5-dibromoaniline using a modified Sandmeyer methodology. The modified Sandmeyer methodology has also been found to be beneficial for the synthesis of other α-isonitrosoacetanilides. The 4,6-dibromohydroxyoxindole nucleus was further confirmed by comparison with the isomeric 5,7-dibromohydroxyoxindole.
- Garden, Simon J.,Torres, Jose C.,Ferreira, Alexandre A.,Silva, Rosangela B.,Pinto, Angelo C.
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- Discovery of di-indolinone as a novel scaffold for protein tyrosine phosphatase 1B inhibitors
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A series of di-indolinone derivatives was designed and synthesized to optimize our lead compounds basing on molecular docking study as PTP1B inhibitors. Successive enzymatic assay identified the synthetic di-indolinone as novel PTP1B inhibitors with low micromole-ranged inhibitory activity and at least several-fold selectivity over other tested homologous PTPs.
- Dai, Hou-Ling,Gao, Li-Xin,Yang, Ying,Li, Jing-Ya,Cheng, Jia-Gao,Li, Jia,Wen, Ren,Peng, Yan-Qing,Zheng, Jian-Bin
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- Study on synthesis of some substituted N-propargyl isatins by propargylation reaction of corresponding isatins using potassium carbonate as base under ultrasound- and microwave-assisted conditions
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Substituted N-propargyl isatins were synthesized by SN2 reaction of corresponding substituted isatins with propargyl bromide in the presence of anhydrous K2CO3 as base. We reported about study on systematically synthesis of these compounds using heating procedures under different reaction conditions, including microwave-assisted heating conditions at power of 100?W (Procedure A), conventional heating conditions in water bath at 50?°C in acetonitrile (Procedure B), and conventional heating conditions in water bath at 50?°C in DMF (procedure C). The best procedure A was deduced based on the investigations on the reaction conditions. Almost all substituted N-propargyl isatins were new, except compounds with R of H, 5-Me, 5-Cl and 5-Br substituents. The structures of the obtained compounds were confirmed by the modern spectroscopic methods.
- Tri, Nguyen Minh,Thanh, Nguyen Dinh,Ha, Luong Ngoc,Anh, Dang Thi Tuyet,Toan, Vu Ngoc,Giang, Nguyen Thi Kim
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p. 4793 - 4801
(2021/05/31)
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- Bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof
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The invention discloses a bicyclic heteroaryl compound with PAR4 antagonistic activity and application thereof. The invention provides the bicyclic heteroaryl compound with PAR4 antagonistic activity,and the bicyclic heteroaryl compound has remarkable antagonistic activity on PAR4 in an in-vitro anti-platelet aggregation experiment, so that platelet aggregation is effectively inhibited, and the bicyclic heteroaryl compound can be used for preparing medicines for preventing or treating various thromboembolic diseases.
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Paragraph 0074-0077
(2020/08/02)
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- Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents
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The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1-42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.
- Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Teli, Divya M.,Patel, Kishan B.,Gandhi, Pallav M.,Patel, Sagar P.,Chaudhary, Bharat N.,Shah, Dharti B.,Prajapati, Navnit K.,Patel, Kirti V.,Yadav, Mange Ram
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p. 3557 - 3574
(2020/11/18)
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- Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
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Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 μM, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
- Aneja, Babita,Khan, Nashrah Sharif,Khan, Parvez,Queen, Aarfa,Hussain, Afzal,Rehman, Md. Tabish,Alajmi, Mohamed F.,El-Seedi, Hesham R.,Ali, Sher,Hassan, Md. Imtaiyaz,Abid, Mohammad
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p. 840 - 852
(2019/01/04)
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- Palladium(II)/N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/Alkylation: Access to 3,3-Disubstituted Oxindoles
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Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential α-arylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions.
- Reddy Panyam, Pradeep Kumar,Ugale, Bharat,Gandhi, Thirumanavelan
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supporting information
p. 7622 - 7632
(2018/06/22)
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- Synthesis and cytotoxic studies of novel 5-phenylisatin derivatives and their anti-migration and anti-angiogenic evaluation
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A number of 5-arylisatin derivatives were synthesized in 5–6 steps from readily available starting materials. Their structures were confirmed by 1H NMR and 13C NMR as well as LC/MS. The cytotoxicity of these novel isatins against human leukemia K562 cells were evaluated by MTT assay in vitro. SAR studies indicated that the N-substituted benzyl and C-5 substituted phenyl groups greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 present in the parent ring is required to maintain such a potency. Particularly, N-(p-methoxybenzyl)-5-(p-methoxyphenyl)isatin (compound 2m) showed the highest antitumor activity against K562 cell lines (IC50 = 0.03 μM). Moreover, treatment with compound 2m significantly inhibited liver cancer HepG2 cells proliferation and migration, which could also reduce the human umbilical vein endothelial cells (HUVEC) tube formation. In conclusion, compound 2m exhibited very good cancer cells proliferation inhibition by angiogenesis responses in vitro, and 2m might be a promising angiogenesis inhibitor for cancer treatment.
- Zhang, Qian,Teng, Yuou,Yuan, Yuan,Ruan, Tingting,Wang, Qi,Gao, Xing,Zhou, Yao,Han, Kailin,Yu, Peng,Lu, Kui
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p. 800 - 814
(2018/07/29)
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- 3-(morpholine substituted aromatic imido) indole compound, preparation method thereof and application
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The invention provides a 3-(morpholine substituted aromatic imido) indole compound which is simple in structure and simple and convenient in synthesis method. In activity tests, some compounds show a certain anti-Kv1.5 biological activity and selectivity, the compound T16 shows high inhibition ratio (IR=70.8%) at the level of 100 micrometers, and the compound T5 also shows a certain inhibitory activity (IR=57.5%) at the level of 100 micrometers. Besides, the compound has a certain target selectivity for a Kv1.5 channel. The invention further provides a preparation method of the 3-(morpholine substituted aromatic imido) indole compound and an application of the compound to preparation, design and development of atrial fibrillation treating medicines.
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Paragraph 0046; 0047; 0048; 0049
(2017/09/05)
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- Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipole and Abnormal [3 + 2]-Cycloaddition with Maleimide in the Presence of 1,4-Diazabicyclo[2.2.2]octane
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A new isatin N,N′-cyclic azomethine imine synthon was devised, and an unexpected abnormal [3 + 2]-cycloaddition with maleimide catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) has been disclosed. A variety of tricyclic spiropyrrolidine oxindoles bearing a dinitrogen heterocycle and succinimide scaffold were obtained in excellent yields (up to 96%) and diastereoselectivities (up to 97:3) under mild conditions.
- Wang, Xiao,Yang, Peng,Zhang, Yong,Tang, Chao-Zhe,Tian, Fang,Peng, Lin,Wang, Li-Xin
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supporting information
p. 646 - 649
(2017/02/10)
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- Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare
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In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50?=?10.4?μM but less cytotoxic activity with IC50?=?141.2?μM (against HepG2 cell line) and 161.2?μM (against human hepatic L02?cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C.?orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure–activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.
- Delong, Wang,Lanying, Wang,Yongling, Wu,Shuang, Song,Juntao, Feng,Xing, Zhang
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p. 286 - 307
(2017/03/09)
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- Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease
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With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC50 values about 44.67–169.80 nM (donepezil IC50 50.12 nM). Notably, compound 12 presented potent activities against PDE5A with IC50 values about 50 μM (sildenafil IC50 12.59 μM), and some of these compounds showed low cell toxicity to A549 cells in vitro.
- Zhou, Li-yun,Zhu, Yao,Jiang, Yu-ren,Zhao, Xiong-jie,Guo, Dong
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p. 4180 - 4184
(2017/08/23)
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- Design, synthesis and biological evaluation of 2-phenylquinoline-4-carboxamide derivatives as a new class of tubulin polymerization inhibitors
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A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2 μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.
- Zhu, Li,Luo, Kaixiu,Li, Ke,Jin, Yi,Lin, Jun
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p. 5939 - 5951
(2017/10/13)
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- Design, synthesis and antiproliferative activity of novel benzothiazole derivatives conjugated with semicarbazone scaffold
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Two series of novel benzothiazole derivatives conjugated with semicarbazone scaffold were designed and synthesized through a structure-based molecular hybridization strategy. All the target compounds were evaluated for their cytotoxicity in vitro against three cancer cell lines (HT-29, MKN-45 and H460) by standard MTT assay. The pharmacological results indicated that seven compounds (17h-n) exhibited comparable or even better antiproliferative activity in comparison with reference drugs Sorafenib and PAC-1. Particularly, compound 17i displayed remarkable cytotoxicity against tested three cancer cell lines with IC50 values of 0.84, 0.06 and 0.52 μM, which were 4.3-, 36.6-, 4.2-folds more potent than Sorafenib and 1.2-, 13.7-, 6.9-times more active than PAC-1, respectively.
- Bao, Guanglong,Du, Baoquan,Ma, Yuxiu,Zhao, Meng,Gong, Ping,Zhai, Xin
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p. 489 - 498
(2016/07/19)
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- Synthesis and anti-cancer activity evaluation of 5-(2-carboxyethenyl)-isatin derivatives
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A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro. SAR study suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of it's mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells.
- Teng, Yu-Ou,Zhao, Hong-Ye,Wang, Jing,Liu, Huan,Gao, Mei-Le,Zhou, Yao,Han, Kai-Lin,Sun, Hua,Yu, Peng,Fan, Zhen-Chuan,Zhang, Yong-Min
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p. 145 - 156
(2018/05/02)
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- A novel strategy to the synthesis of 4-anilinoquinazoline derivatives
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A novel approach to prepare 4-anilinoquinazoline derivatives based on the transformation of indoline-2,3-dione to formamidine was developed. The processes with this approach are simple, efficient, and environmentally friendly. The efficiency of this approach was evaluated by synthesizing 17 4-anilinoquinazolines and comparing the obtained yields with those achievable through conventional synthetic methods. It was the first time that compounds 8d, 8e, 8h, and 13b-f were synthesized. The characteristics of the IR and the UV spectra of these compounds and the effects of their substituents on the spectra were observed.
- Wang, Zheng,Wang, Cuiling,Sun, Yanni,Zhang, Ning,Liu, Zhulan,Liu, Jianli
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p. 906 - 913
(2014/01/23)
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- Structure-based design, synthesis, andanticonvulsant activity of isatin-1-N-phenylacetamide derivatives
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In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1- yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED50 of 91.3 mg/kg, TD50 of >1,000 mg/kg, a higher protective index (PI = TD50/ED50, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore. Springer Science+Business Media 2013.
- Xie, Chao,Tang, Li-Ming,Li, Fu-Nan,Guan, Li-Ping,Pan, Cheng-Yan,Wang, Si-Hong
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p. 2161 - 2168
(2014/05/06)
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- Design, synthesis and antiproliferative activity evaluation of new 5-azaisoindigo derivatives
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New 5-azaisoindigo derivatives were synthesized with two key intermediates 5-azaoxindole (7) and substituted indole-2,3-dione (10) in this paper. Intermediate 7 was prepared from 3-methylpyridine (1) through 6 steps containing oxidation reaction and so on. Intermediate 10 was obtained by a convenient Sandmeyer's method. The target compounds 5-azaisoindigo derivatives 11a-f were obtained by condensation of these two intermediates 7 and 10 in acidic condition. All target compounds were evaluated for their antiproliferative activity against seven cell lines by SRB assay. Compounds 11e and 11f showed significant antiproliferative activity against K562 cells (IC50: 8.9 μM and 13.6 μM, respectively).
- Zhao, Ping,Yan, Yun,Li, Yanzhong,Zhang, Aiying,Zhan, Xiaoping,Liu, Zenglu,Mao, Zhenmin,Chen, Shaoxiong,Wang, Liqun
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p. 1923 - 1932
(2014/08/18)
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- Design, synthesis and evaluation of quinoline-based small molecule inhibitor of stat3
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As STAT3 has been validated as an anticancer target, its inhibitors have been shown to possess therapeutic promise for the treatment of human cancers. To identify novel and selective STAT3 inhibitors, a virtual screening based on the STAT3 SH2 domain was performed and a small molecule, 2-phenylquinoline-4- carboxylic acid (5a), with an inhibition constant Ki value of 17.53 iM to STAT3 was discovered. On this basis, the derivatives of 5a including esters, amides and dimers were synthesized. The bioactivity and inhibitory selectivity of the derivatives were assayed using human breast cancer cell lines, MDA-MB-468 and MCF-7. Among the derivatives, 5c and 9b showed the most potent inhibitory activity with a good selectivity, and also inhibited STAT3 protein level of MDA-MB-468 cells. The results demonstrated a successful application of virtual screening for lead discovery. Compound 9b might be an effective STAT3 inhibitor lead for the further development of antitumor agents.
- Shi, Zhi-Bing,Zhang, Lei,Bin, Zheng-Yang,Cao, Xiang-Rong,Gong, Zhu-Nan,Li, Jian-Xin
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p. 420 - 426
(2013/07/26)
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- Novel indoline-2,3-dione derivatives as inhibitors of aminopeptidase N (APN)
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Aminopeptidase N (APN/CD13), as a zinc-containing ectoenzyme, plays a critical role in the process of tumor angiogenesis, invasion and metastasis. Through the docking-based virtual screening of chemical databases and the further activity assay, we discovered that compound 10c exhibits potent and selective inhibitory ability towards APN. In addition, a series of indoline-2,3-dione derivates have been designed and synthesized as APN inhibitors. The results of preliminary activity evaluation showed that compound 12a (IC50 = 0.074 ± 0.0026 μM) exhibited the best inhibitory activity against APN, which could be used for further anticancer agent research.
- Jin, Kang,Zhang, Xiaopan,Ma, Chunhua,Xu, Yingying,Yuan, Yumei,Xu, Wenfang
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p. 2663 - 2670
(2013/06/27)
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- Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in lewis lung cancer (LLC) tumor-bearing mice
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Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3 + regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.
- Yang, Shuangshuang,Li, Xishuai,Hu, Fangfang,Li, Yinlong,Yang, Yunyun,Yan, Junkai,Kuang, Chunxiang,Yang, Qing
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supporting information
p. 8321 - 8331
(2013/12/04)
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- Synthesis of spiro[furan-3,3′-indolin]-2′-ones by PET-catalyzed [3+2] reactions of spiro[indoline-3,2′-oxiran]-2-ones with electron-rich olefins
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An efficient procedure for the synthesis of spiro[furan-3,3′-indolin] -2-ones and dispiro[cycloalkane-1,2′-furan-3′,3″-indolin]- 2″-ones has been achieved in high yields and stereoselectivity by photoinduced electron transfer-catalyzed [3+2] reactions of substituted spiro[indoline-3,2′-oxiran]-2-ones with olefins. The reactions proceed by ring opening of spiro[indoline-3,2′-oxiran]-2-ones via C β-O bond cleavage and subsequent cycloaddition with olefins by using 2,4,6-triphenylpyrylium tetarfluoroborate (TPT) as a sensitizer.
- Wang, Lihong,Li, Zhanshan,Lu, Lianhong,Zhang, Wei
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supporting information; experimental part
p. 1483 - 1491
(2012/03/09)
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- Discovery, Synthesis, and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 9,10-Dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one Scaffold
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West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B-NS3 protease inhibitor with a 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold was identified by screening a small library of non-peptidic compounds. This initial hit was optimized by solution-phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor (1a40, IC50=5.41±0.45μM) of WNV NS2B-NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the Senantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)-1a40 is a preferred isomer for inhibition of WNV NS3 protease.
- Samanta, Sanjay,Cui, Taian,Lam, Yulin
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experimental part
p. 1210 - 1216
(2012/08/08)
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- Synthesis and biological evaluation of novel indolin-2-one derivatives as protein tyrosine phosphatase 1b inhibitors
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3-Substituted indolin-2-one derivatives had been designed and synthesized as a novel class ofprotein tyrosine phosphatase 1B (PTP1B) inhibitors. These compounds had been evaluated for their inhibitory activities against PTP1B in vitro with IC50 values in a low micromolar range.Compound 36, the lowest, bore an IC50 value of 3.48 μM. Preliminary structure-activity relationship was summarized.
- Dai, Hou-Ling,Shen, Qiang,Zheng, Jian-Bin,Lib, Jing-Ya,Wen, Ren,Li, Jia
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scheme or table
p. 526 - 530
(2012/04/23)
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- Synthesis, characterization, antitumor, and cytotoxic activity of mononuclear Ru(II) complexes
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In the search for antitumor active metal complexes several ruthenium complexes have been reported to be promising. A series of mononuclear Ru(II) complexes, [Ru(T)2(S)]2+, where T = 2,2'-bipyridine/1,10- phenanthroline and S = CH3-bitsz, Cl-bitsz, Br-bitsz, tmtsz, dmtsz, have been prepared and characterized by UV-Vis, IR, 1H-NMR, FAB-mass spectroscopy, and elemental analysis. The complexes were subjected to invivo anticancer activity against a transplantable murine tumor cell line Ehrlich's ascitic carcinoma (EAC) and invitro cytotoxic activity against human cancer cell line Molt 4/C8, CEM, and murine tumor cell line L1210. Ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascitic cell counts. Treatment with these complexes prolonged the life span of EAC-tumor-bearing mice by 10-48%. Invitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 mol L -1 against Molt 4/C8, 0.16-19 μmol L-1 against CEM, and 0.75-32 μmol L-1 against L1210 cell proliferation, depending on the nature of the compound.
- Thota, Sreekanth,Karki, Subhas Somalingappa,Jayaveera,Balzarini, Jan,Clercq, Erik De
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scheme or table
p. 4332 - 4346
(2011/09/12)
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- DIHYDROOROTATE DEHYDROGENASE INHIBITORS
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The invention relates to compounds of formula (I) wherein R1, R2, X1, X2, Y, Ra, Rb, Q have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis and also in the treatment of cancer disorders.
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Page/Page column 77
(2010/11/03)
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- Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl] methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors
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Fourteen new 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives were synthesized. Six compounds displayed potent inhibitory activities against COX-1/2 and 5-LOX with IC50 in the range of 0.10-9.87 μM. Particularly, 10f exhibited well balanced inhibitory action on these enzymes (IC50 = 0.10-0.56 μM). More importantly, 10f and several other compounds had comparable or stronger anti-inflammatory and analgesic activities, but better gastric tolerability in vivo, as compared with darbufelone mesilate and tenidap sodium. Therefore, our findings may aid in the design of new and safe anti-inflammatory reagents for the intervention of painful inflammatory diseases, such as rheumatoid arthritis at clinic.
- Lai, Yisheng,Ma, Lin,Huang, Wenxing,Yu, Xing,Zhang, Yihua,Ji, Hui,Tian, Jide
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scheme or table
p. 7349 - 7353
(2011/01/12)
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- Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3- trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors
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The trifluoromethyl group (CF3) is present in commercially available drugs of various therapeutic classes owing to its ability to modify and frequently improve their biological activities. Efavirenz is a trifluoromethylated inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) that shows good results in anti-HIV chemotherapy. With the objective of developing efficient non-nucleoside compounds, we have designed and synthesized some new 3-hydroxy-2-oxo-3-trifluoromethylindole as potential RT inhibitors. We used different substituted isatins as starting materials. The final products contain the group CF3, present in Efavirenz, and a pharmacophoric group, oxoindole. We have used molecular docking with HIV-1 RT as a tool to design putative non-nucleoside reverse transcriptase inhibitors (NNRTIs). Based on the calculation results obtained, a series of new 3-hydroxy-2-oxo-3-trifluoromethylindoles were synthesized as a novel class of potential RT inhibitors. The results showed that these compounds are capable of important interactions with the NNRT binding site, which encouraged us to submit them for biological assay. All compounds studied are significantly active in the RNA-dependent DNA-polymerase (RDDP) assay, and were not toxic toward the Vero cell line. Hence, the designed molecules represent good starting structures for further modification and structure-activity relationship (SAR) studies. Birklaewser 2007.
- Boechat, Nubia,Kover, Warner B.,Bastos, Monica M.,Romeiro, Nelilma C.,Silva, Alessa S. C.,Santos, Fernanda C.,Valverde, Alessandra L.,Azevedo, Maria L. G.,Wollinger, Wagner,Souza, Thiago M. L.,De Souza, Silmara Lucia Oliveira,De Frugulhetti, Izabel Christina P. P.
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p. 492 - 510
(2008/04/01)
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- An improved synthesis of isonitrosoacetanilides
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A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N- phenylacetamides] has been developed, involving the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochloride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and those containing electron rich ortho-substituents, neither of which react well under traditional conditions.
- Rewcastle, Gordon W.,Sutherland, Hamish S.,Weir, Claudette A.,Blackburn, Adrian G.,Denny, William A.
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p. 8719 - 8721
(2007/10/03)
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- Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase
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A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC50 880 μM) whereas several members of the series inhibited PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in the diisopropylamides that inhibited PfDHODH.
- Boa, Andrew N.,Canavan, Shane P.,Hirst, Paul R.,Ramsey, Christopher,Stead, Andrew M.W.,McConkey, Glenn A.
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p. 1945 - 1967
(2007/10/03)
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- Preparation, characterization and antimicrobial properties of some palladium and platinum complexes with active Schiff base ligands
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The synthetic, spectroscopic and biological studies of some palladium and platinum complexes derived from 5-methyl-1,3-dihydro-3-[2-(phenyl)ethylidene]- 2H-indol-2-one-hydrazinecarbothioamide(L1H) and 5-methyl-1,3-dihydro- 3-[2-(phenyl)ethylidene]-2H-indol-2-one-hydrazinecarboxamide(L2H) are reported here. These complexes have been characterized on the basis of elemental analysis, molecular weight determinations and spectral studies including IR, 1H NMR and electronic spectra. The resulting coloured products are monomeric in nature. On the basis of the above studies, square planar geometry has been proposed for the resulting complexes. Both the ligands and their complexes have been screened for their fungicidal and bactericidal activities and the results indicate that they exhibit significant antimicrobial properties.
- Biyala, Mukesh Kumar,Fahmi, Nighat,Singh
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p. 2536 - 2541
(2007/10/03)
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- Synthesis, characterization and pharmacological screening of some isatinoid compounds
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Schiff bases and hydrazones of substituted isatins have been prepared by reacting isatin and the appropriate aromatic primary amine l hydrazines and characterized by spectral and elementary analysis. The compounds have been screened for analgesic, antiinflammatory and antipyretic activity. 3[(4-Bromo phenylidene)-1-amino] isatin is the only compound to exhibit all the activities. 3[(4-Bromo phenylidene)-1-amino] isatin and 3[(4- Bromo phenylidene)-1-amino]-5-methyl isatin possesses analgesic activity equipotent to paracetamol. 3(4-Phenylhydrazino) isatin and 3(thiosemicarbazino) isatin exhibit marked reduction of acetic acid induced inflammation. 3[(4-Methyl phenylidene)-1-amino] isatin at 200 mg/kg exhibits pronounced antipyretic activity comparable to paracetamol.
- Sridhar,Ramesh
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p. 668 - 672
(2007/10/03)
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- Synthesis and characterization of six-coordinated cis-MoO2 (VI) complexes with heterocyclic ketimines, containing O, N and N,S donors
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The synthesis and characterization of four six-coordinated cis- dioxomolybdenum(VI) complex of hydrazinecarboxamides and hydrazinecarbothioamides of the general formula cis-MoO2(L)2 are reported. Spectroscopic (IR, UV, 1H, 13NMR and XRD spectral studies) and other analytical data reveal that the ligands react with dioxobis(2,4-pentanedionato)-molybdenum(VI) in 2:1 molar ratio to give diamagnetic molybdenum(VI) mononuclear complex. The compounds have been tested in vitro and in vivo against a number of fungal and bacterial strains.
- Gupta, Neeti,Singh
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- Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors
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A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'- halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'- chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure- activity relationships in this series are also discussed.
- Yamagishi,Yamada,Ozaki,Asao,Shimizu,Suzuki,Matsumoto,Matsuoka,Matsumoto
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p. 2085 - 2094
(2007/10/02)
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