- Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile
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Discovery of novel and potent lead molecules for the specific therapeutic targets by de novo drug design is still in infancy. Here, we disclose the unprecedented development of imidazopyri(mi)dine-based tumor pyruvate kinase M2 (PKM2) modulators by subseq
- Patel, Sagarkumar,Globisch, Christoph,Pulugu, Priyanka,Kumar, Prasoon,Jain, Alok,Shard, Amit
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- 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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- N-Acylbenzotriazole: convenient approach for protecting group-free monoacylation of symmetric diamines
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Abstract: An efficient green route for monoacylation of aromatic diamines, namely o-phenylenediamine and p-phenylenediamine and aliphatic diamines ethylenediamine and piperazine using N-acylbenzotriazoles (NABs) in n-butanol was developed. The new protocol does not require prior selective protection of the diamine and comprises simple conditions, short reaction times, an easy work up as well as high isolated yields (69–94%). Moreover, the method described herein enable stepwise acylation of aliphatic diamines such as ethylenediamine and piperazine with two different N-acylbenzotriazoles affording unsymmetrical substituted diamines that can be used for construction of pharmaceutically important targets such as drugs, foldamers, and drug conjugates. Graphic abstract: [Figure not available: see fulltext.]
- Agha, Khalid A.,Abo-Dya, Nader E.,Ibrahim, Tarek S.,Abdel-Aal, Eatedal H.,Abdel-Samii, Zakaria K.
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p. 589 - 598
(2020/05/06)
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- Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms
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We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeu
- Mancuso, Francesca,Di Fiore, Anna,De Luca, Laura,Angeli, Andrea,Monti, Simona M.,De Simone, Giuseppina,Supuran, Claudiu T.,Gitto, Rosaria
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supporting information
p. 1000 - 1005
(2020/03/23)
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- Design, synthesis, and biological evaluation of matrine derivatives possessing piperazine moiety as antitumor agents
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Using matrine (1) as the lead compound, a series of new piperazinyl matrine derivatives were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Structure activity relationship (SAR) analysis indicated that introductio
- Xu, Yiming,Liang, Pengyun,Rashid, Haroon ur,Wu, Lichuan,Xie, Peng,Wang, Haodong,Zhang, Shuyan,Wang, Lisheng,Jiang, Jun
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p. 1618 - 1627
(2019/07/29)
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- NMR-based investigations of acyl-functionalized piperazines concerning their conformational behavior in solution
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Selected N-benzoylated piperazine compounds were synthesized to study their conformational behavior using temperature-dependent 1H NMR spectroscopy. All investigated piperazines occur as conformers at room temperature resulting from the restric
- Wodtke, Robert,Steinberg, Janine,K?ckerling, Martin,L?ser, Reik,Mamat, Constantin
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p. 40921 - 40933
(2019/01/03)
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- Substituted O-hydroxyphenyl ketone compound as well as preparation method and application thereof
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The invention discloses a substituted O-hydroxyphenyl ketone compound, a preparation method of the substituted O-hydroxyphenyl ketone compound, and an application of the substituted O-hydroxyphenyl ketone compound to preparation of a BRD4 protein activity
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Paragraph 0100; 0102; 0109-0111
(2018/11/22)
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- Tankyrase inhibitor
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The invention belongs to the technical field of medicines and particularly relates to a tankyrase inhibitor represented by a general formula (I) shown in the description and pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, wherein R1, R2, R3, m, n, Z, L, Q, A, X1, X2 and Y are as defined in the description. The invention further relates to a preparation method for the compounds, pharmaceutical preparations and pharmaceutical compositions containing the compounds and application of the compound and the pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparation of drugs for treating and/or preventing tankyrase mediated cancers and related diseases.
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Paragraph 0358-0360
(2017/10/13)
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- Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3β Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators
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Recent studies reveal that glycogen synthase kinase-3β (GSK-3β) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was
- Tantray, Mushtaq A.,Khan, Imran,Hamid, Hinna,Alam, Mohammad Sarwar,Dhulap, Abhijeet,Ganai, Ajaz Ahmad
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- ALPHA-SYNUCLEIN LIGANDS
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The present invention generally relates to various compounds that are useful as α-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson's disease (PD).
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Paragraph 0178
(2017/08/01)
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- A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines
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The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.
- Conroy, Trent,Manohar, Madhura,Gong, Yu,Wilkinson, Shane M.,Webster, Michael,Lieberman, Brian P.,Banister, Samuel D.,Reekie, Tristan A.,Mach, Robert H.,Rendina, Louis M.,Kassiou, Michael
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p. 9388 - 9405
(2016/10/13)
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- Synthesis, characterization, and anti-inflammatory activities of methyl salicylate derivatives bearing piperazine moiety
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In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.
- Li, Jingfen,Yin, Yong,Wang, Lisheng,Liang, Pengyun,Li, Menghua,Liu, Xu,Wu, Lichuan,Yang, Hua
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- Expanding the structural diversity of Bcr-Abl inhibitors: Hybrid molecules based on GNF-2 and Imatinib
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In order to expand the structural diversity of Bcr-Abl inhibitors, twenty hybrids (series E and P) have been synthesized and characterized based on Imatinib and GNF-2. Their biological activities were evaluated in vitro against human leukemia cells. Most compounds exhibited potent antiproliferative activity against K562 cells, especially for compounds E4, E5 and E7. Furthermore, these new hybrids were also screened for Abl kinase inhibitory activity, and some of them inhibited Abl kinase with low micromolar IC50 values. In particular, compound P3 displayed the most potent activity with IC50 value of 0.017 μM comparable with that of Imatinib. Molecular docking studies indicated that these novel hybrids fitted well with the active site of Bcr-Abl. These results suggested the great potential of these compounds as novel Bcr-Abl inhibitors.
- Pan, Xiaoyan,Dong, Jinyun,Shao, Ruili,Su, Ping,Shi, Yaling,Wang, Jinfeng,He, Langchong
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supporting information
p. 4164 - 4168
(2015/11/03)
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- Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)- 2H-phthalazin-1-ones as potent PARP-1 inhibitors
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We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H- phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
- Wang, Ling-Xiao,Zhou, Xin-Bo,Xiao, Meng-Liang,Jiang, Ning,Liu, Feng,Zhou, Wen-Xia,Wang, Xiao-Kui,Zheng, Zhi-Bing,Li, Song
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p. 3739 - 3743
(2014/09/17)
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- Aminolysis of S-4-nitrophenyl X-substituted thiobenzoates: Effect of nonleaving-group substituents on reactivity and mechanism
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A kinetic study is reported for aminolysis of S-4-nitrophenyl X-substituted thiobenzoates 3a-g in 80 mol % H2O/20 mol % DMSO at 25.0 ± 0.1 °C. Thiol esters 3a-g are 7.8-47.6 fold more reactive than the corresponding oxygen esters (i.e., 4-nitrophenyl X-substituted benzoates 1a-g). Such reactivity order appears to be in accordance with the expectation that 4-nitrothiophenoxide in 3a-g is a better nucleofuge than 4-nitrophenoxide in 1a-g since the former is 2.64 pKa units less basic than the latter. Hammett plot for the reactions of 3a-g exhibit poor correlation coefficients (R2 = 0.977-0.986) with negative deviation by substrates possessing an electrondonating group (EDG), while the Yukawa-Tsuno plots result in excellent linear correlation (R2 = 0.995-0.997) with ? = 0.93-1.23 and r = 0.57-0.67, indicating that the negative deviation shown by substrates possessing an EDG is caused by ground-state stabilization through resonance interactions but not due to a change in ratedetermining step upon changing the nonleaving-group substituent X. The p value increases as the incoming amine becomes more basic and more reactive, indicating that the RSP is not operative in the current reactions.
- Im, Li-Ra,Jeon, Sang-Eun,Um, Ik-Hwan
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experimental part
p. 1153 - 1157
(2011/11/12)
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- Direct synthesis of N-acylalkylenediamines from carboxylic acids under mild conditions
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Monoacylated piperazine derivatives were prepared directly from carboxylic acids and piperazine using triphenylphosphine (TPP) and N-bromosuccinimide (NBS) in dichloromethane. Inexpensive and readily available reagents, excellent yields, short reaction times and mild reaction conditions are important features of this method.
- Bandgar,Bettigeri
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p. 2917 - 2924
(2007/10/03)
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- Highly rapid and direct synthesis of monoacylated piperazine derivatives from carboxylic acids under mild conditions
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A series of monoacylated piperazine derivatives were obtained by the reaction of carboxylic acids with 2-chloro-4,6-dimethoxy-1,3,5-triazine in dichloromethane at room temperature. Good to excellent yields, short reaction times and mild reaction conditions are important features of this methodology.
- Bandgar,Pandit
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p. 3855 - 3858
(2007/10/03)
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- NOVEL QUINAZOLINE DERIVATIVES
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Quinazoline derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof in said formula R1is nitro or halogen; R2and R4are each hydrogen, C1-4alkyl, carboxyl, or C2-5alkoxycarbonyl; R3is hydrogen, amino, optionally substituted C1-4alkyl, C1-4alkanoyl, or C2-5alkoxycarbonyl; W is carbon or nitrogen; and m is 0 to 2.
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- Study of synthesis and cardiovascular activity of some furoxan derivatives as potential NO-donors
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A series of hybrid molecules incorporating the furoxan and nicorandil moieties were designed as potential NO donors with cardiovascular and cerebrovascular activities. Thirty-six target molecules were successfully synthesized by conventional methods and characterized by infrared spectroscopy, 1H-NMR spectroscopy and high resolution mass spectra. The compounds were tested for their effects on KCl-induced contraction of rabbit thoracic aorta whose endothelium was denuded. Eight compounds were found to reduce KCl-induced contraction by more than 30% at 10 μM. All except one of these compounds are characterized by the presence of electron withdrawing groups in the phenyl ring attached via an amide or ester linkage to the furoxan moiety. The nature of the terminal carbonyl linkage (ester or amide) and the length or type of the alkyl chain bridging the two carbonyl functions have little effect on the activity. One of the active compounds, N-(4- methoxy-benzoyl)-N'-[3-methylfuroxanyl-4-carbonyl)piperazine (17i) was tested for hypotensive effects on anaesthetized rats at 1.5 mg/kg, and found to demonstrate a gradual and sustained hypotensive effect. The results suggest that the furoxannicorandil derivatives are a useful lead in the design of NO- donor compounds for hypertension.
- Mu, Li,Feng, Si-Shen,Go, Mei Lin
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p. 808 - 816
(2007/10/03)
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- Effect of Acyl Substituents on the Reaction Mechanism for Aminolyses of 4-Nitrophenyl X-Substituted Benzoates
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Second-order rate constants (kN) have been measured spectrophotometrically for the reaction of 4-nitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol % dimethyl sulfoxide at 25.0°C.
- Um, Ik-Hwan,Min, Ji-Sook,Ahn, Jung-Ae,Hahn, Hyun-Joo
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p. 5659 - 5663
(2007/10/03)
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- Structure-reactivity correlations in the reaction of 2,4-dinitrophenyl X-substituted benzoates with alicyclic secondary amines
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Apparent second-order rate constants (kapp) have been measured spectrophotometrically for the reaction of 2,4-dinitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol% DMSO at 25°C. The microconstants involved in the reaction (k-1/k2, K1, and k1k2/k-1) have also been calculated. The magnitude of kapp, k1, and k1k2/k-1 values increases with increasing amine basicity and with increasing acid strengthening ability of the acyl substituent X. The k-1/k2 value decreases from ca. 6.5 to 0.3 with increasing the amine basicity, but remains almost constant upon changing the acyl substituent X for a given amine, indicating that the ratedetermining step is governed by the basicity of amine but not by the electronic nature of the acyl substituent X. The Bronsted-type plots for kapp show a break at pKa = 9.1, supporting the assumption that a change in the rate-determining step occurs from rate-limiting breakdown to formation of the addition intermediate as amine basicity increases. The corresponding Bronsted-type plots for k-1/k2, k1, and k1k2/k-1 are linear but their β values are different. σ+ constants show better correlation with log kapp, log kl and log k1k2/k-1 for the reaction with low basic amines (pKa a > 9.1). The magnitude of ρ1 is identical to that of ρapp and ρeq for a given amine.
- Um, Ik-Hwan,Min, Ji-Sook,Lee, Hye-Won
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p. 659 - 666
(2007/10/03)
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