- 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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- Co-sensitization of the HD-2 complex with low-cost cyanoacetanilides for highly efficient DSSCs
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The photophysical and electrochemical properties of new targeted 2-cyanoacetanilide-based dyes are illustrated. New cyanoacetanilides SA7-10 were synthesized and employed as co-sensitizers in DSSCs. The chemical structures of these 2-cyanoacetanilides differ according to the substituent at the benzene ring (-H,-Me,-OMe and-NEt2), with the anchoring moiety being the same, a-COOH group. Furthermore, a density functional theory (DFT) calculation has shown an effective intermolecular charge transfer character, the HOMOs of SA7-10 are mainly located on the corresponding donor part, and their LUMOs are located on carboxylic acid moieties as the acceptor. Interestingly, using photosensitizers SA7-10 as co-sensitizers with HD-2 dye causes an improvement in their photovoltaic performances. Among the dyes, SA10 co-sensitized with HD-2 displayed an overall efficiency of 8.25%, a JSC of 19.5 mA cm-2, a VOC of 0.65 V and an FF of 64.35 compared to 7.46%, 19 mA cm-2, 0.64 V and 60.54, respectively, of HD-2 only. Moreover, the electrochemical impedance spectroscopy (EIS) data of SA7-10 and HD-2 were found to be in accordance with the obtained photovoltaic parameters. Finally, the results indicated that 2-cyanoacetanilide-based dyes were utilized as promising co-sensitizers due to their easy preparation methods and their relatively small size.
- Elmorsy, Mohamed R.,Lyu, Luping,Su, Rui,Abdel-Latif, Ehab,Badawy, Safa A.,El-Shafei, Ahmed,Fadda, Ahmed A.
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p. 281 - 288
(2020/03/03)
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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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- 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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- 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, 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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supporting information
p. 844 - 851
(2019/03/26)
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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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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
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- Synthesis of some novel thieno[3,2-d]pyrimidines as potential cytotoxic small molecules against breast cancer
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A variety of novel thieno[3,2-d]pyrimidines with different decorating functional groups were synthesized as a part of a study aiming to enrich the arsenal of chemotherapeutic agents for the treatment of cancer. The design of synthetic molecules based on DNA-interchelating properties by hydrogen bond formation. The reported compounds herein are: 4-aminothienopyrimidine derivatives 4a, b and their 4-substituted phenylamino analogues 8a, b; 4-thienopyrimidin-4-ones 5a, b; N-alkyl thienopyrimidin-4-ones 6a-g; 4-chlorothienopyrimidines 7a, b and thienopyrimidoquinazolinones 9a, b which are the structural mimics of 8a, b. The synthesized molecules were evaluated for their in vitro cytotoxic activity against human breast cancer cell line (MCF-7). Biological screening revealed varying cytotoxic potencies of the tested molecules compared with Doxorubicin as a reference drug. The cytotoxicity results from the study suggested that the synthesized molecules are potential antitumor agents and compound 4a was the most potent with an IC50 2.04 nM.
- Kandeel, Manal,Abdelhameid, Mohammed Kamal,Eman, Kamal,Labib, Madlen Berty
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p. 637 - 647
(2013/07/27)
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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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- Synthesis and evaluation of 2-chloromethyl-3-N-substituted arylthieno (2,3-d)pyrimidin-4-ones and derivatives for central nervous system depressant activity
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2-Chloromethyl 3-N-substituted arylthieno (2,3-d)pyrimidin-4-ones and derivatives were synthesized by reacting 2-amino-3-carboxanilido-4,5,6,7-tetrahydrobenzo(b)thiophenes (I(abc)) with chloroacetyl chloride in dioxane and by cyclizing the open chain 3-su
- Manjunath, Kadthala Shekar,Mohan, Shamanna,Naragund, Laxmi Venkatesh Gurachar,Shishoo, Chamanlal Jagannath
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p. 1005 - 1008
(2007/10/03)
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