- Synthesis, characterization, and docking studies of novel cyanopyridone analogs with serotonin 5-HT1B receptor agonists
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The medications in use for treating migraine are directed either towards inhibiting the characteristic migraine pain or towards preventing it from occurring. In this pursuit, ergotamine and sumatriptan class of 5-HT1B receptor agonists have been proved to be extremely effective. Further research into this field led us to design cyanopyridone derivatives that were synthesized through cyclization of 2-cyano-N-phenylacetamides with malonitrile and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. The synthesized cyanopyridones analogs, when docked with active site of 5-HT1B receptor, showed better binding affinity compared to standard antimigraine medications. Additionally, in silico ADME prediction for drug-likeness and pharmacokinetics revealed that all compounds are safer and can be used as antimigraine medicine. The structure of the synthesized compounds has been elucidated on the basis of spectral analysis.
- Baitha, Amresh,Upadhyay, Manish,Gopinathan, Ajay,Krishnan, Karthik,Dabholkar, Vijay V.
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- Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones
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The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.
- Wen, Li-Rong,Wang, Ning-Ning,Du, Wu-Bo,Ma, Qiang,Zhang, Lin-Bao,Li, Ming
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supporting information
p. 2895 - 2900
(2021/04/14)
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- Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma
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Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
- Liang, Xuewu,Sun, Chenxia,Li, Chunpu,Yu, Haolan,Wei, Xiaohui,Liu, Xuyi,Bao, Wei,Shi, Yuqiang,Sun, Xiaochen,Khamrakulov, Mirzadavlat,Yang, Chenghua,Liu, Hong
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p. 9217 - 9237
(2021/07/20)
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- Oxidative Photochlorination of Electron-Rich Arenes via in situ Bromination
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Electron-rich arenes are oxidatively photochlorinated in the presence of catalytic amounts of bromide ions, visible light, and 4CzIPN as organic photoredox catalyst. The substrates are brominated in situ in a first photoredox-catalyzed oxidation step, followed by a photocatalyzed ipso-chlorination, yielding the target compounds in high ortho/para regioselectivity. Dioxygen serves as a green and convenient terminal oxidant. The use of aqueous hydrochloric acid as the chloride source reduces the amount of saline by-products.
- Düsel, Simon Josef Siegfried,K?nig, Burkhard
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supporting information
p. 1491 - 1495
(2019/04/30)
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- Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
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Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.
- Gerndt, Susanne,Chen, Cheng-Chang,Chao, Yu-Kai,Yuan, Yu,Burgstaller, Sandra,Rosato, Anna Scotto,Krogsaeter, Einar,Urban, Nicole,Jacob, Katharina,Nguyen, Ong Nam Phuong,Miller, Meghan T.,Keller, Marco,Vollmar, Angelika M.,Gudermann, Thomas,Zierler, Susanna,Schredelseker, Johann,Schaefer, Michael,Biel, Martin,Malli, Roland,Wahl-Schott, Christian,Bracher, Franz,Patel, Sandip,Grimm, Christian
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- Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
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Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).
- Endo, Satoshi,Oguri, Hiroaki,Segawa, Jin,Kawai, Mina,Hu, Dawei,Xia, Shuang,Okada, Takuya,Irie, Katsumasa,Fujii, Shinya,Gouda, Hiroaki,Iguchi, Kazuhiro,Matsukawa, Takuo,Fujimoto, Naohiro,Nakayama, Toshiyuki,Toyooka, Naoki,Matsunaga, Toshiyuki,Ikari, Akira
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p. 10396 - 10411
(2020/11/02)
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- From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
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The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC50s of 0.53 and 2.90 μM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre.
- Massari, Serena,Corona, Angela,Distinto, Simona,Desantis, Jenny,Caredda, Alessia,Sabatini, Stefano,Manfroni, Giuseppe,Felicetti, Tommaso,Cecchetti, Violetta,Pannecouque, Christophe,Maccioni, Elias,Tramontano, Enzo,Tabarrini, Oriana
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- Synthesis, anti-varicella-zoster virus and anti-cytomegalovirus activity of 4,5-disubstituted 1,2,3-(1H)-triazoles
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Background: Clinical drugs for herpesvirus exhibit high toxicity and suffer from significant drug resistance. The development of new, effective, and safe anti-herpesvirus agents with different mechanisms of action is greatly required. Objective: Novel inhibitors against herpesvirus with different mechanisms of action from that of clinical drugs. Methods: A series of novel 5-(benzylamino)-1H-1,2,3-triazole-4-carboxamides were efficiently synthesized and EC50 values against Human Cytomegalovirus (HCMV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were evaluated in vitro. Results: Some compounds present antiviral activity. Compounds 5s and 5t are potent against both HCMV and VZV. Compounds 5m, 5n, 5s, and 5t show similar EC50 values against both TK+ and TK? VZV strains. Conclusion: 5-(Benzylamino)-1H-1, 2,3-triazole-4-carboxamides are active against herpesviruses and their activity is remarkably affected by the nature and the position of substituents in the benzene ring. The results indicate that these derivatives are independent of the viral thymidine kinase (TK) for activation, which is indispensable for current drugs. Their mechanisms of action may differ from those of the clinic anti-herpesvirus drugs.
- Yuan, Wei-Yuan,Chen, Xue,Liu, Ning-Ning,Wen, Yi-Ning,Yang, Bei,Andrei, Graciela,Snoeck, Robert,Xiang, Yu-Hong,Wu, Yong-Wei,Jiang, Zhen,Schols, Dominique,Zhang, Zhuo-Yong,Wu, Qin-Pei
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p. 801 - 812
(2019/11/02)
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- 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
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Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
- Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
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supporting information
p. 179 - 192
(2019/01/04)
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- Structure-based design, synthesis and biological evaluation of a newer series of pyrazolo[1,5-a]pyrimidine analogues as potential anti-tubercular agents
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In-depth study of structure-based drug designing can provide vital leads for the development of novel, clinically active molecules. In this present study, twenty six novel pyrazolo[1,5-a]pyrimidine analogues (6a-6z) were designed using molecular docking studies. The designed molecules were synthesized in good yields. Structural elucidation of the synthesized molecules was carried out using IR, MS, 1H NMR and 13C NMR spectroscopy. All the synthesized compounds were evaluated for their in-vitro anti-tubercular activity against H37Rv strain by Alamar Blue assay method. Most of the synthesized compounds displayed potent anti-tubercular activities. Amongst all the tested compounds 6p, 6g, 6n and 6h exhibited promising anti-tubercular activity. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study. None of these compounds exhibited potent cytotoxicity. Stability of protein ligand complex was further evaluated by molecular dynamics simulation for 10 ns. All these results indicate that the synthesized compounds could be potential leads for further development of new potent anti-tubercular agents.
- Modi, Palmi,Patel, Shivani,Chhabria, Mahesh
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p. 240 - 251
(2019/03/26)
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- Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides
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The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 μM).
- Demjén, András,Alf?ldi, Róbert,Angyal, Anikó,Gyuris, Márió,Hackler, László,Szebeni, Gábor J.,W?lfling, János,Puskás, László G.,Kanizsai, Iván
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- Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
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With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18–1.2 μM) at no toxic concentrations (CC50 > 250 μM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents.
- Desantis, Jenny,Nannetti, Giulio,Massari, Serena,Barreca, Maria Letizia,Manfroni, Giuseppe,Cecchetti, Violetta,Palù, Giorgio,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
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p. 128 - 139
(2017/07/03)
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- Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)
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Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure-activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of ~30 nM, ~3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.
- Truong, Eric C.,Phuan, Puay W.,Reggi, Amanda L.,Ferrera, Loretta,Galietta, Luis J. V.,Levy, Sarah E.,Moises, Alannah C.,Cil, Onur,Diez-Cecilia, Elena,Lee, Sujin,Verkman, Alan S.,Anderson, Marc O.
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supporting information
p. 4626 - 4635
(2017/06/13)
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- AMINO-SUBSTITUTED HETEROCYCLIC DERIVATIVES AS SODIUM CHANNEL INHIBITORS
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The present invention relates to novel aminoindazolyl derivative compounds of Formula(I), the use of said compounds in treating diseases mediated by modulation of voltage-gated sodium channels in particular Nav1.7 AND to compositions containing said derivatives.
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Page/Page column 60
(2016/11/17)
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- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
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Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
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p. 7487 - 7499
(2015/07/15)
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- Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1
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Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.
- Hu, Dawei,Miyagi, Namiki,Arai, Yuki,Oguri, Hiroaki,Miura, Takeshi,Nishinaka, Toru,Terada, Tomoyuki,Gouda, Hiroaki,El-Kabbani, Ossama,Xia, Shuang,Toyooka, Naoki,Hara, Akira,Matsunaga, Toshiyuki,Ikari, Akira,Endo, Satoshi
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p. 7487 - 7499
(2015/11/27)
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- One pot synthesis of novel cyanopyridones as an intermediate of bioactive pyrido[2,3-d]pyrimidines
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Synthesis, structural characterization, and biological activity studies of novel pyrido[2,3-d]pyrimidines (10a-h, 11a-h) are described. Cyclization of cynoacetamides (4, 5) with malonitrile (7) and aldehyde (6a-h) via Hantzsch pyridine synthesis afforded cyanopyridones (8a-h, 9a-h), which on cyclization with formic acid under microwave conditions led to the final product. All the reactions are significantly faster and the isolated yields are remarkably higher in microwave conditions compared to the conventionally heated reactions. The compounds were tested in vitro for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtillus, Staphylococcus aureus, and Micrococcus luteus and antifungal activity against Trichphyton longifusus, Candida albicans, Microsporum canis, Fusarium solani. Compounds 10b, 10e, 11b and 11e exhibited good antibacterial and antifungal activities compared with standards.
- Khatri, Taslimahemad T.,Shah, Viresh H.
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p. 366 - 376
(2014/08/18)
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- A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines
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A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently synthesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)acrylamides and selected β-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a β-keto ester to 2-cyano-3,3-bis(methylthio) acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3- (methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine.
- Kumar, Sukeerthi,Thakur, Rajni R.,Margal, Sanjay R.,Thomas, Abraham
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supporting information
p. 5112 - 5118
(2013/06/27)
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- Synthesis of some substituted isoxazolo [5,4-d] pyrimidine-4(5H)-ones and their biological evaluation
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Substituted anilines vk'ere condensed Wiih ethyl cyanoacetate in xylene to get corresponding 2-cyano-N-phenylacetamides 1a-1h, which upon reaction with sodium bicarbonate and acetic anhydride gave corresponding compounds 2-cyano-3-hydroxy-N-phenylbut-2-enamides 2a-2h, which further upon reaction with hydroxyl amine hydrochloride in methanol yielded corresponding 5-amino-3-methyl-N-phenylisoxazole-4-carboxamides 3a-3h. 3a-3h when treated with acetic anhydride and triethyl orthoformate, gave substituted isoxazolo [5,4-d] pyrimidin-4 (5H)-ones 4a-4h.
- Godhani,Kaila,Sanghani,Dobariya
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p. 225 - 228
(2013/09/24)
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- Synthesis and insecticidal activities of novel neonicotinoid analogs bearing an amide moiety
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Figure represented. A series of novel neonicotinoid analogs containing an amide moiety were synthesized, characterized, and subsequently evaluated for their insecticidal activity. According to the preliminary bioassay, the compounds 6c, 6e, 6f, 6j, 6n, and 6r exhibited > 50% activity against Nilaparvata lugens at 100 mg/L. Amongst the active compounds, 6f and 6r revealed insecticidal activities similar to that displayed by standard buprofezin. J. Heterocyclic Chem., (2011)
- Wu, Jian,Yang, Song,Song, Bao-An,Bhadury, Pinaki S.,Hu, De-Yu,Zeng, Song,Xie, Hua-Peng
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scheme or table
p. 901 - 906
(2011/10/02)
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- 3,4-Disubstituted isothiazoles: Novel potent inhibitors of VEGF receptors 1 and 2
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Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (>30 × 10-5 cm/min) across Caco-2 cell monolayer.
- Kiselyov, Alexander S.,Semenova, Marina,Semenov, Victor V.
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scheme or table
p. 1195 - 1198
(2009/08/07)
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- ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2
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We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 30 × 10-5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.
- Kiselyov, Alexander S.,Piatnitski, Evgueni L.,Samet, Alexander V.,Kisliy, Victor P.,Semenov, Victor V.
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p. 1369 - 1375
(2007/10/03)
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- Synthesis of N-substituted γ-methylene γ-lactams
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N-Substituted cyanoacetamides 1 were condensed with 1,2-diketones 2 under base catalysis to form ?-hydroxy ?-lactams 3. Treatment of 3 with acids gave novel fungicidal ?-methylene ?-lactams 4. The exocyclic double bond of 4b reacted reversibly with 4-toluene sulfinate. CSIRO 2005.
- Adhikari, Raju,Jones, Dionne A.,Liepa, Andris J.,Nearn, Roland H.
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p. 882 - 890
(2007/10/03)
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- Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl- 3-hydroxy. N-[3'-methyl-4'-(trifluoromethyl)phenyl]propenamide and related compounds
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The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.
- Kuo, Elizabeth A.,Hambleton, Philip T.,Kay, David P.,Evans, Phillip L.,Matharu, Saroop S.,Little, Edward,McDowall, Neil,Jones, C. Beth,Hedgecock, Charles J. R.,Yea, Christopher M.,Chan, A. W. Edith,Hairsine, Peter W.,Ager, Ian R.,Tully, W. Roger,Williamson, Richard A.,Westwood, Robert
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p. 4608 - 4621
(2007/10/03)
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- Synthesis and Biological Activity of a Series of Diaryl-Substituted α-Cyano-β-hydroxypropenamides, a New Class of Anthelmintic Agents
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A series of α-cyano-β-hydroxypropenamides was prepared and tested for anthelmintic activity. α-Cyano-β-hydroxy-N--3-propenamide (1) showed good activity against the nematode Nematospirodes dubius in a mixed parasite infection in mice; several of the analogues were also effective against the cestode Hymenolepis nana.In sheep trials, 1 caused 100percent reduction of the hematophagous nematode Haemonchus contortus after a single dose of 20 mg/kg but did not show satisfactory control of Trichostrongylus colubriformis or Ostertagia circumcincta.Against the liver fluke Fasciola hepatica, 1 suppressed egg production but only temporarily, suggesting that the adult flukes were not eliminated.Mechanism of action studies on 1 using Ascaris mitochondria showed it to be an uncoupler of oxidative phosphorylation.
- Sjogren, Eric B.,Rider, Michael A.,Nelson, Peter H.,Bingham, Stanford,Poulton, Anthony L.,et al.
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p. 3295 - 3301
(2007/10/02)
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- SYNTHESIS OF 2-AMINO-1-AZIRINES AND THEIR REACTIONS WITH CARBOXYLIC ACIDS
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A method was developed for the synthesis of 2-amino-1-azirines under the conditions of a modified Neber reaction.Their reactivities with respect to mono- and dicarboxylic acids and thiocarboxylic acids were investigated.
- Eremeev, A. V.,Piskunova, I. P.,El'kinson, R. S.
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p. 998 - 1002
(2007/10/02)
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