- Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
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Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 12089 - 12108
(2021/09/06)
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- Zirconium-hydride-catalyzed site-selective hydroboration of amides for the synthesis of amines: Mechanism, scope, and application
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Developing mild and efficient catalytic methods for the selective synthesis of amines is a longstanding research objective. In this respect, catalytic deoxygenative amide reduction has proven to be promising but challenging, as this approach necessitates selective C–O bond cleavage. Herein, we report the selective hydroboration of primary, secondary, and tertiary amides at room temperature catalyzed by an earth-abundant-metal catalyst, Zr-H, for accessing diverse amines. Various readily reducible functional groups, such as esters, alkynes, and alkenes, were well tolerated. Furthermore, the methodology was extended to the synthesis of bio- and drug-derived amines. Detailed mechanistic studies revealed a reaction pathway entailing aldehyde and amido complex formation via an unusual C–N bond cleavage-reformation process, followed by C–O bond cleavage.
- Han, Bo,Jiao, Haijun,Wu, Lipeng,Zhang, Jiong
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p. 2059 - 2067
(2021/09/02)
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- Synthesis and muscarinic acetylcholine receptor (mAChR) antagonist activity of substituted piperazine-triazoles
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This study describes synthesis of a series of piperazine-triazole derivatives and their ex vivo evaluation for preliminary muscarinic acetylcholine receptor (mAChR) blocking activity on rat ileum model. A molecule based on benzonitrile piperazine triazole scaffold showed good tissue relaxation and blocking of neurotransmitter ACh in the ex vivo experiment. Graphic abstract: [Figure not available: see fulltext.]
- Acharya, Badri Narayan,Ghorpade, RamaRao,Singh, Kshetra Pal,Kumar, Deo,Nayak, Sabita
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p. 357 - 366
(2021/03/16)
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- Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein
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Respiratory syncytial virus (RSV) is the main cause of lower respiratory tract diseases in infants and young children, with potentially serious and fatal consequences associated with severe infections. Despite extensive research efforts invested in the identification of therapeutic measures, no vaccine is currently available, while treatment options are limited to ribavirin and palivizumab, which both present significant limitations. While clinical and pre-clinical candidates mainly target the viral fusion protein, the nucleocapsid protein or the viral polymerase, our focus has been the identification of new antiviral compounds targeting the viral M2-1 protein, thanks to the presence of a zinc-ejecting group in their chemical structure. Starting from an anti-RSV hit we had previously identified with an in silico structure-based approach, we have designed, synthesised and evaluated a new series of dithiocarbamate analogues, with which we have explored the antiviral activity of this scaffold. The findings presented in this work may provide the basis for the identification of a new antiviral lead to treat RSV infections.
- Bassetto, Marcella,Benato, Sara,Brancale, Andrea,Ferla, Salvatore,Jochmans, Dirk,Manganaro, Roberto,Neyts, Johan,Paulissen, Jasmine
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supporting information
(2020/03/13)
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- Genipin analogue, preparation method and application thereof
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The invention relates to the field of pharmaceutical chemistry, and in particular relates to genipin analogues (I) and medicinal salts containing the genipin analogues, a preparation method and pharmaceutical compositions containing the genipin analogues or the medicinal salts. Pharmacodynamic tests prove that the compounds provided by the invention can be used for preventing and treating neurodegenerative diseases such as Alzheimer.
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Paragraph 0035-0036; 0043-0045
(2020/08/30)
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- Development of 2-amino-4-phenylthiazole analogues to disrupt myeloid differentiation factor 88 and prevent inflammatory responses in acute lung injury
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Myeloid differentiation primary response protein 88 (MyD88), an essential adapter protein used by toll-like receptors (TLR), is a promising target molecule for the treatment of respiratory inflammatory diseases. Previous studies explored the activities of novel 2-amino-4-phenylthiazole analogue (6) in inflammation-induced cancer, and identified the analogue as an inhibitor of MyD88 toll/interleukin-1 receptor (TIR) homology domain dimerization. Here, we describe the synthesis of 47 new analogues by modifying different sites on this lead compound and assessed their anti-inflammatory activities in lipopolysaccharide-induced mouse primary peritoneal macrophages (MPMs). The most promising compound, 15d, was found to effectively interact with MyD88 protein and prevented formation of the MyD88 homodimeric complex. Furthermore, 15d showed in vivo anti-inflammatory activity in LPS-caused model of acute lung injury. This work provides new candidates as MyD88 inhibitors to combat inflammation diseases.
- Chen, Lingfeng,Chen, Hongjin,Chen, Pengqin,Zhang, Wenxin,Wu, Chao,Sun, Chuchu,Luo, Wu,Zheng, Lulu,Liu, Zhiguo,Liang, Guang
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- Design, synthesis, and evaluation of genipin derivatives for the treatment of Alzheimer's Disease
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Twenty-two novel genipin derivatives have been designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this series with IC50 value of 218?nm. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid β-protein 1–42 (Aβ1–42). Among them, 8a showed higher inhibition rate (%Inhibition?=?22.29) than the positive reference Donepezil (%Inhibition?=?17.65).
- Huang, Weijun,Wang, Yujun,Li, Jiaming,Zhang, Yanchun,Ma, Xiaodong,Zhu, Panhu,Zhang, Yang
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p. 110 - 122
(2018/12/11)
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- The synthesis and biological evaluation of novel gardenamide A derivatives as multifunctional neuroprotective agents
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A novel series of gardenamide A derivatives was synthesized as potential anti-Alzheimer's disease agents. The neuroprotective effects of these multifunctional agents against oxygen-glucose deprivation (OGD)-induced neurotoxicity in rat cortical neurons, and hydrogen peroxide (H2O2)- A nd amyloid-β1-42 (Aβ1-42)-induced neurotoxicity in rat hippocampal neurons were evaluated. In vitro studies revealed that these compounds demonstrated moderate to good multifunctional neuroprotective activity. Among the entire series, compounds 10e, 10j, 10n and 10p appeared to be the most active multifunctional neuroprotective agents. Studies indicate that compounds 10e, 10f, 10h, 10i, 10j, 10n and 10p exhibit significant activities against OGD-induced neurotoxicity in rat cortical neurons, and 10e, 10j, 10n and 10p show prominent activities against H2O2- A nd Aβ1-42-induced neurotoxicity in rat hippocampal neurons. Moreover, these derivatives did not exert conspicuous neurotoxicity in rat cortical neurons. Thus, the present study evidently shows that 10e, 10j, 10n and 10p are potent multifunctional neuroprotective agents, which may serve as promising lead candidates for anti-Alzheimer's disease drug development.
- Zhang, Zuzhi,Wang, Yujun,Zhang, Yanchun,Li, Jiaming,Huang, Weijun,Wang, Lei
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p. 1180 - 1186
(2019/07/25)
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- Design, Synthesis, and Cytotoxic Evaluation of Certain 7-Chloro-4-(piperazin-1-yl)quinoline Derivatives as VEGFR-II Inhibitors
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Signaling pathway inhibition of VEGFR-II is visualized as valuable tool in cancer management. In the current study, the synthesis of novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)-ethanone derivatives (4a–t) was achieved through the amination of 2-chloro-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (3) with different secondary amines. The structures of the target compounds were confirmed by IR, 1H-NMR, 13C-NMR, HRMS, and microanalysis. Compounds 4a–t were subjected to in vitro anticancer screening against human breast cancer (MCF-7) and prostate cancer (PC3) cell lines. The highest cytotoxicty against both cell lines was displayed by 2-(4-(4-bromobenzyl)piperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q), with IC50 values of 6.502 and 11.751 μM against MCF-7 and PC3 cells, respectively, compared with the standard drug doxorubicin (MCF-7: 6.774 μM, PC3: 7.7316 μM). Due to its notable activity toward MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC50 of 1.38 μM compared to sorafenib (0.33 μM). The docking study proved that 4q has a binding mode akin to that of VEGFR-II inhibitors.
- Aboul-Enein, Mohamed Nabil,El-Azzouny, Aida M. Abd El-Sattar,Ragab, Fatma Abdel-Fattah,Hamissa, Mohamed Farouk
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- Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of alzheimer's disease
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(A.H.); Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder characterized by memory loss, language impairment, personality changes and intellectual decline. Taking into account the key pathological features of AD, such as low levels of acetylcholine, beta-amyloid (Aβ) aggregation, oxidative stress and dyshomeostasis of biometals, a new series of paeonol derivatives 5a-5d merging three different functions, i.e., antioxidant, anti-acetylcholinesterase (AChE) activity, metal chelating agents for AD treatment have been synthesized and characterized. Biological assays revealed that compared with paeonol (309.7 μM), 5a-5d had a lower DPPH IC50 value (142.8-191.6 μM). 5a-5d could significantly inhibit hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay in the concentration range of 5-40 μM. AChE activity was effectively inhibited by 5a-5d, with IC50 values in the range of 0.61-7.04 μM. 5a-5d also exhibited good metal-chelating ability. All the above results suggested that paeonol derivatives may be promising multifunctional agents for AD treatment.
- Zhou, An,Wu, Hongfei,Pan, Jian,Wang, Xuncui,Li, Jiaming,Wu, Zeyu,Hui, Ailing
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p. 1304 - 1318
(2015/01/30)
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- Zwitterionic-surfactant-stabilized palladium nanoparticles as catalysts in the hydrogen transfer reductive amination of benzaldehydes
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Palladium nanoparticles (NPs) stabilized by a zwitterionic surfactant are revealed here to be good catalysts for the reductive amination of benzaldehydes using formate salts as hydrogen donors in aqueous isopropanol. In terms of environmental impact and e
- Drinkel, Emma E.,Campedelli, Roberta R.,Manfredi, Alex M.,Fiedler, Haidi D.,Nome, Faruk
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p. 2574 - 2579
(2014/04/17)
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- PROCASPASE-ACTIVATING COMPOUNDS AND COMPOSITIONS
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The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.
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Paragraph 0088; 0129-0130
(2013/04/24)
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- Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors
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Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition.
- Zhang, Cunlong,Tan, Chunyan,Zu, Xuyu,Zhai, Xin,Liu, Feng,Chu, Bizhu,Ma, Xiaohua,Chen, Yuzong,Gong, Ping,Jiang, Yuyang
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experimental part
p. 1404 - 1414
(2011/04/22)
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- Synthesis and biological activity of new 1-[4-(substituted)-piperazin-1- ylmethyl]-1H-benzotriazole
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A new kind of benzotriazole derivatives has been designed and synthesised. The structures of all of the title compounds were characterised by 1H NMR, IR, MS and elemental analyses. Herbicidal activities of the benzotrizole derivatives were evaluated with barnyard grass and rape cup and KARI tests. The results showed that compounds exhibited weak herbicidal activities against barnyardgrass and rape and KARI enzyme.
- He, Feng-Qi,Liu, Xing-Hai,Wang, Bao-Lei,Li, Zheng-Ming
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p. 809 - 811
(2007/10/03)
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- BICYCLIC PIPERAZINE COMPOUND AND USE THEREOF
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The present invention provides a compound represented by the formula: wherein R1 is an acyl group, R2 is a hydrocarbon group which may be substituted or the like, R3 is a hydrocarbon group which may be substituted or the like, R4 is a hydrocarbon group which may be substituted or the like, n is from 0 to 4, and X is an oxygen atom, a sulfur atom or the like, or a salt thereof. The invention also provides a compound which has a TGR23 antagonist activity and thus is useful for prevention and treatment of cancer.
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Page/Page column 53
(2010/11/08)
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- Synthesis and preliminary pharmacological evaluation of 4′-arylmethyl analogues of clozapine. I - The effect of aromatic substituents
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As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4′-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Taylor, David A.
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p. 565 - 576
(2007/10/03)
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- ISOXAZOLE AND PYRAZOLE DERIVATIVES AS DOPAMINE RECEPTOR SUBTYPE LIGANDS
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A class of substituted isoxazole and pyrazole derivatives of formula (I), or a salt thereof of or a prodrug thereof, wherein the broken circle represents two non-adjacent double bonds whereby the five-membered ring containing X and Y is aromatic; one of X and Y represents nitrogen, and the other of X and Y represents oxygen or N--R 5 ; R. sup.1 represents hydrogen, C 1-6 alkyl or trifluoromethyl; R 2 and R 3 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro,--OR a,--SR a,--SOR a,--SO 2 R a,--SO 2 NR. sup.a R b,--NR a R. sup.a,--NR a CO 2 R b,--COR a,--CO 2 R a or--CONR a R b, R 4 represents hydrocarbon or a heterocyclic group; R 5 represents hydrogen or C 1-6 alkyl; and R a and R. sup.b independently represent hydrogen, hydrocarbon or a heterocyclic group, are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment and/or prevention of disorders of the dopamine system, in particular schizophrenia. STR1
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- Piperazine derivatives
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Compounds of the formula (I), or pharmaceutically acceptable salts thereof STR1 wherein X is phenyl, optionally substituted by one halogen, C1-4 alkyl or C1-4 alkoxy; or pyridyl; R1 is hydrogen or C1-6 alkyl; an
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- 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-substituted-piperazines
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This disclosure describes novel 1-(5-amino-4H-1,2,4-triazol-3-yl)-4-substituted-piperazines which are useful as hypotensive agents in mammals.
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