- Synthesis of Novel Bi-Heterocycles as Valuable Anti-Diabetic Agents: 2-({5-((2-Amino-1,3-Thiazol-4-yl)methyl)-1,3,4-Oxadiazol-2-yl}sulfanyl)-N-(Substituted)acetamides
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Abstract: The synthesis of a new series of S-substituted acetamides derivatives of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol were synthesized and evaluated for enzyme inhibition study along with cytotoxic behavior. Ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate was converted to corresponding acid hydrazide by hydrazine hydrate in ethanol. The reflux of acid hydrazide with carbon disulfide resulted to 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol. Different electrophiles were synthesized by the reaction of respective anilines (one in each reaction) and 2-bromoacetylbromide in an aqueous medium. The targeted bi-heterocyclic compounds were synthesized by stirring nucleophilic 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol with different acetamides electrophiles (one after another), in DMF using LiH as base and activator. The proposed structures of newly synthesized compounds were deduced by spectroscopic techniques such as 1H NMR, 13C NMR, EI MS and elemental analysis. These novel bi-heterocycles were tested for their anti-diabetic potential via the in vitro inhibition of α-glucosidase enzyme. The in silico study of these molecules was also coherent with their enzyme inhibition data. Furthermore, these molecules were analyzed for their cytotoxic behavior against brine shrimps. It was inferred from the results that most of them exhibited very potent inhibitory potential against the studied enzyme and can be utilized as valuable anti-diabetic agent.
- Aziz-ur-Rehman,Khan, Farman Ali,Lodhi, Muhammad Arif,Mirza, Bushra,Muhammad, Athar Abbasi,Ramzan, Muhammad Shahid,Shah, Syed Adnan Ali,Siddiqui, Sabahat Zahra
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- Optimising the relaxivities of Mn2+ complexes by targeting human serum albumin (HSA)
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We report two novel macrocyclic ligands based on the 1,4-DO2AM platform (1,4-DO2AM = 2,2′-(1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetamide) and containing two benzyl groups attached either to the nitrogen atoms of the macrocyclic unit (1,4-BzDO2AM) or to the amide pendant arms (1,4-DO2AMBz). The protonation constants of the ligands and the stability constants of their Mn2+ complexes were determined using pH potentiometry. The introduction of benzyl groups results in a slight decrease of the stability constants of the Mn2+ complexes and a slight increase of their acid-catalysed dissociation reactions. A detailed relaxometric characterisation of the complexes using nuclear magnetic dispersion relaxation (NMRD) and 17O NMR studies indicated that the increase in molecular weight associated with the presence of benzyl groups results in a remarkable increase of proton relaxivities r1p, which take values of 3.8, 3.5 and 2.5 mM-1 s-1 for [Mn(1,4-BzDO2AM)]2+, [Mn(1,4-DO2AMBz)]2+ and [Mn(1,4-DO2AM)]2+ (at 25 °C and 20 MHz). The [Mn(1,4-BzDO2AM)]2+ and [Mn(1,4-DO2AMBz)]2+ complexes form relatively strong adducts with Human Serum Albumin (HSA) with association constants of (3.9 ± 0.6) × 103 and (2.0 ± 0.3) × 103 M-1, respectively. The interaction with the protein slows down the rotational tumbling of the complex in solution, which results in adducts endowed with remarkably high proton relaxivities (r1pb = 18.5 ± 0.7 and 27.4 ± 1.4 mM-1 s-1 for [Mn(1,4-BzDO2AM)]2+ and [Mn(1,4-DO2AMBz)]2+, respectively).
- Forgács, Attila,Tei, Lorenzo,Baranyai, Zsolt,Esteban-Gómez, David,Platas-Iglesias, Carlos,Botta, Mauro
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- Gold-Catalyzed Unexpected Ring Transformation of Pyrimidodiazepine Derivatives
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Pyrimidodiazepine derivatives underwent an unexpected gold-catalyzed retro-Mannich-type carbon-carbon bond cleavage and intramolecular nucleophilic cyclization. The pyrimidodiazepines bearing an alkyne moiety showed novel orthogonal reactivity in the presence of a gold catalyst, as opposed to the alkynophilicity that is commonly observed with gold catalysts. The ring transformation reaction of pyrimidodiazepines probably proceeds through an acyclic iminium intermediate. The potential of this synthetic method for the skeletal diversification of pyrimidine-containing macrocycles was also demonstrated.
- Koo, Jaeyoung,Kim, Jonghoon,Park, Seung Bum
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- Fluorescent analogs of peptoid-based HDAC inhibitors: Synthesis, biological activity and cellular uptake kinetics
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Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 2, 6-((N-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-N-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 2 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 2 might contribute to its potent anti-proliferative properties.
- Raudszus, Rick,Nowotny, Robert,Gertzen, Christoph G.W.,Sch?ler, Andrea,Krizsan, Andor,Gockel, Ines,Kalwa, Hermann,Gohlke, Holger,Thieme, René,Hansen, Finn K.
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- Synthesis and antiviral activity of a series of novel quinoline derivatives as anti-RSV or anti-IAV agents
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We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC50 = 3.10–6.93 μM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC50: 2490.33 μM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (IC50s: 1.87–14.28 μM) were more active against IAV than or comparable to ribavirin (IC50: 15.36 ± 0.93 μM). Particularly, the most active compound 1ae (IC50: 1.87 ± 0.58 μM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.
- Wang, Minghua,Zhang, Guoning,Zhao, Jianyuan,Cheng, Ningning,Wang, Yujia,Fu, Yuanhui,Zheng, Yanpeng,Wang, Juxian,Zhu, Mei,Cen, Shan,He, Jinsheng,Wang, Yucheng
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- Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies
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Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 μM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 μM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.
- Muzaffar, Saima,Shahid, Wardah,Riaz, Naheed,Saleem, Muhammad,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Kaleem, Ayesha,al-Rashida, Mariya,Baral, Bikash,Bhattarai, Keshab,Gross, Harald
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- BENZYLAMIDE DERIVATIVES AS INHIBITORS OF TRANSFORMING GROWTH FACTOR-BETA RECEPTOR I/ALK5
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The present invention relates to novel benzylamide derivatives of formula (I) to processes for the preparation of said compounds; to pharmaceutical compositions comprising said compounds and to said compounds for use in the treatment of pathological conditions or diseases that can improve by inhibition of transforming growth factor-β receptor I (TGFβRI)/ALK5, such as diseases and disorders associated to fibrotic conditions of gastrointestinal system, skin and eyes, to methods for the treatment and/or prevention of said diseases or pathological conditions and to combinations comprising said compounds and further comprising therapeutically effective amounts of other therapeutic agents useful for the treatment of said diseases or pathological conditions.
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(2021/06/04)
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- Exploring the synthesis and characterization of fac-Re(CO)3L complexes using diethylenetriamine derivative functionalized at the central nitrogen
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The aim of this research is to develop new rhenium complexes with favorable bio-distribution properties which can be used as radiometal complexes or for conjugation with biomolecules for the development of targeted radiolabelled biopharmaceuticals. Two metals of interest utilized in radiopharmaceuticals are technetium and rhenium, both of which share similar chemical and structural properties. The coordination chemistry of these metals is highly dependent upon ligands that are structurally and chemically robust among other factors. The synthesis of new symmetrical tridentate ligands and ligand conjugation methods will expand the likelihood of developing suitable fac-[Re(CO)3L]n compounds with promising biomedical properties and were consequently the subject of this investigation. In order to accomplish this, the design, synthesis, characterization and X-ray structure of new water-soluble rhenium complexes for assessing metal binding to biomolecules were investigated. Three diethylenetriamine (dien) derivatives, 2-(bis(2-aminoethyl)amino)-N-(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)acetamide (atfcdien, 3), 2-(bis(2-aminoethyl)amino)-N-(3,5-bis(trifluoromethyl)benzyl)acetamide (tfmedien, 6), and N-benzyl-2-(bis(2-aminomethyl)amino)acetamide (badien, 9) and their rhenium complexes were synthesized. 1H NMR spectroscopy, mass spectrometry and X-ray crystallography techniques were employed to characterize the ligands and their rhenium complexes [Re(CO)3atfcdien]Br (10), [Re(CO)3tfmedien]Br (11) and [Re(CO)3badien]Br (12). 1H NMR studies were conducted to examine chelated Re complexes revealed a consistent downfield shift of the CH signal of the dien moiety for all three new ligands.
- Ndinguri, Margaret W.,Black, Carrie A.,Gosser, Anna L.,Reitz, Sara,Sutphin, Cody,Fronczek, Frank R.,Cormier, Lindsay E.
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- Synthesis and in Vitro Evaluation of Novel 5-Nitroindole Derivatives as c-Myc G-Quadruplex Binders with Anticancer Activity
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Lead-optimization strategies for compounds targeting c-Myc G-quadruplex (G4) DNA are being pursued to develop anticancer drugs. Here, we investigate the structure-activity- relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine-substituted 5-nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5-nitroindole scaffolds bind to the c-Myc promoter G-quadruplex. These compounds downregulate c-Myc expression and induce cell-cycle arrest in the sub-G1/G1 phase in cancer cells. They further increase the concentration of intracellular reactive oxygen species. NMR spectra show that three of the newly synthesized compounds interact with the terminal G-quartets (5′- and 3′-ends) in a 2 : 1 stoichiometry.
- Nimbarte, Vijaykumar D.,Wirmer-Bartoschek, Julia,Gande, Santosh L.,Alshamleh, Islam,Seibert, Marcel,Nasiri, Hamid Reza,Schnütgen, Frank,Serve, Hubert,Schwalbe, Harald
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supporting information
p. 1667 - 1679
(2021/03/24)
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- Discovery of Novel Acetamide-Based Heme Oxygenase-1 Inhibitors with PotentIn VitroAntiproliferative Activity
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Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Accordingly, compounds7iand7l-pemerged for their potency against HO-1 and were investigated for their anticancer activity against prostate (DU145), lung (A549), and glioblastoma (U87MG, A172) cancer cells. The selected compounds showed the best activity toward U87MG cells. Compound7lwas further investigated for its in-cell enzymatic HO-1 activity, expression levels, and effects on cell invasion and vascular endothelial growth factor (VEGF) extracellular release. The obtained data suggest that7lcan reduce cell invasivity acting through modulation of HO-1 expression.
- Fallica, Antonino N.,Sorrenti, Valeria,D’Amico, Agata G.,Salerno, Loredana,Romeo, Giuseppe,Intagliata, Sebastiano,Consoli, Valeria,Floresta, Giuseppe,Rescifina, Antonio,D’Agata, Velia,Vanella, Luca,Pittalà, Valeria
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p. 13373 - 13393
(2021/09/20)
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- Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies
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In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 μM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13–98.21 μM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5–88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential ‘lead’ compounds in drug discovery and development.
- Amjad, Hira,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Bhattarai, Keshab,Imran, Muhammad,Muzaffar, Saima,Riaz, Naheed,Saleem, Muhammad,Shahid, Wardah
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- Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
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Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.
- Ang, Chee Wei,Tan, Lendl,Sykes, Melissa L.,Abugharbiyeh, Neda,Debnath, Anjan,Reid, Janet C.,West, Nicholas P.,Avery, Vicky M.,Cooper, Matthew A.,Blaskovich, Mark A. T.
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p. 15726 - 15751
(2020/12/02)
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- A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: enzyme inhibition and molecular docking studies
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Two series of new N-aryl/aralkyl derivatives (9a–q) of 2-(4-ethyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide and N-aryl/aralkyl derivatives (10a–q) of 2-(4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized. The methods included successive conversions of thiophen-2-acetic acid (a) into its respective ester, hydrazide and N-aryl/aralkyl 1,3,4-triazole. The target compounds (9a–q; 10a–q) were obtained by the reaction of N-aryl/aralkyl 1,3,4-triazole (5, 6) with various electrophiles, (8a–q), in N,N-dimethyl formamide (DMF) and sodium hydroxide at room temperature. The characterization of these compounds was done by FTIR, 1H-, 13C-NMR, EI-MS and HR-EI-MS spectral data. All compounds were evaluated for their enzyme inhibitory potentials against electric eel acetylcholinesterase, AChE (10f, 10d; IC50 values 32.26 ± 0.12, 45.72 ± 0.11?μM, respectively), equine butyrylcholinesterase, BChE (9d, 9l, 9b, 10d, 10h; IC50 values 12.52 ± 0.19, 12.52 ± 0.19, 21.72 ± 0.18, 23.62 ± 0.22, 24.52 ± 0.21?μM, respectively), jack bean urease (10i, 10n, 9e; IC50 values 7.27 ± 0.05, 7.35 ± 0.04, 8.79 ± 0.05?μM, respectively) and yeast α-glucosidase enzymes (9o, 10i; IC50 values 62.94 ± 0.19, and 69.46 ± 0.15?μM, respectively). The molecular docking studies supported these findings. This study provides cheaper bioactive triazole amides as promising future lead molecules.
- Riaz, Naheed,Iftikhar, Muhammad,Saleem, Muhammad,Aziz-ur-Rehman,Ahmed, Ishtiaq,Ashraf, Muhammad,Shahnawaz,Rehman, Jameel,al-Rashida, Mariya
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p. 1183 - 1200
(2020/01/31)
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- Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and molecular simulation
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PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value. Here, based on the compound PubChem CID 8,478,960 (IC50 = 45.01 μM), a series of thiophene [2,3-d] pyrimidine derivatives (IC50 = 0.4–37.87 μM) were discovered as novel and efficient inhibitors of SHP2 through powerful “core hopping” and CDOCKER technology. Furthermore, the SHP2-PTP phosphatase activity assay indicated that Comp#5 (IC50 = 0.4 μM) was the most active SHP2 inhibitor. Subsequently, the effects of Comp#5 on the structure and function of SHP2 were investigated through molecular dynamics (MD) simulation and post-kinetic analysis. The result indicated that Comp#5 enhanced the interaction of residues THR357, ARG362, LYS366, PRO424, CYS459, SER460, ALA461, ILE463, ARG465, THR507 and GLN510 with the surrounding residues, improving the stability of the catalytic active region and the entrance of catalytic active region. In particular, the Comp#5 conjugated with residue ARG362, elevating the efficient and selectivity of SHP2 protein. The study here may pave the way for discovering the novel SHP2 inhibitors for suffering cancer patients.
- Li, Wei-Ya,Ma, Ying,Li, Hao-Xin,Lu, Xin-Hua,Du, Shan,Ma, Yang-Chun,Zhou, Liang,Wang, Run-Ling
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- Regio- and Diastereoselective Access to 4-Imidazolidinones via an Aza-Mannich Initiated Cyclization of Sulfamate-Derived Cyclic Imines with α-Halo Hydroxamates
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An efficient regio- and diastereoselective cyclization of sulfamate-derived cyclic imines with unsubstituted or monosubstituted α-halo hydroxamates is developed under mild conditions. This reaction proceeds smoothly under transition-metal-free conditions via a domino aza-Mannich addition/intramolecular nucleophilic substitution sequence, providing a convenient route to access 2-monosubstituted and 2,5-disubstituted 4-imidazolidinones. Notably, the products were obtained with single trans-isomers in moderate to excellent yields.
- Zhou, Jing,Zhang, Hong,Chen, Xue-Lian,Qu, Ya-Li,Zhu, Qianqian,Feng, Chen-Guo,Chen, Ya-Jing
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p. 9179 - 9187
(2019/08/12)
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- First Nondiscriminating Translocator Protein Ligands Produced from a Carbazole Scaffold
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Development of neuroinflammation agents targeting the translocator protein (TSPO) has been hindered by a common single nucleotide polymorphism (A147T) at which TSPO ligands commonly lose affinity. To this end, carbazole acetamide scaffolds were synthesized and structure activity relationships elaborated to explore the requirements for high-affinity binding to both TSPO wild type (WT) and the polymorphic TSPO A147T. This study reports high binding affinity and nondiscriminating TSPO ligands.
- Cheng, Hei Wun Alison,Sokias, Renee,Werry, Eryn L.,Ittner, Lars M.,Reekie, Tristan A.,Du, Jonathan,Gao, Quanqing,Hibbs, David E.,Kassiou, Michael
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supporting information
p. 8235 - 8248
(2019/10/11)
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- Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies
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The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 μM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.
- Butt, Abdul Rehman Sadiq,Abbasi, Muhammad Athar,Aziz-ur-Rehman,Siddiqui, Sabahat Zahra,Raza, Hussain,Hassan, Mubashir,Shah, Syed Adnan Ali,Shahid, Muhammad,Seo, Sung-Yum
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p. 459 - 472
(2019/02/19)
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- Design, synthesis, fungicidal activity and molecular docking studies of novel 2-((2-hydroxyphenyl)methylamino)acetamide derivatives
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A series of novel 2-hydroxyphenyl substituted aminoacetamides was designed by molecular hybridization of the aminoacetamide scaffold and 2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal activities were evaluated. Some of the target compounds showed excellent antifungal activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e displayed the most potent activity against S. sclerotiorum with EC50 = 2.89 μg/mL, which was lower than that of commercial chlorothalonil. The systematic studies provided strong confidence that the hydroxyl group and the carbonyl group are crucial for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could be one of the potential action targets of our compounds.
- Tang, Zilong,Li, Xinxing,Yao, Yuan,Qi, Yongcun,Wang, Ming,Dai, Ningning,Wen, Yuhao,Wan, Yichao,Peng, Lifen
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p. 2572 - 2578
(2019/03/26)
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- 12N-substituted matrinol derivatives inhibited the expression of fibrogenic genes via repressing integrin/FAK/PI3K/Akt pathway in hepatic stellate cells
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Twenty new 12N-substituted matrinol derivatives were synthesized and evaluated for their inhibitory effects on collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure-activity relationship (SAR) revealed that introducing a 12N-benzeneaminoacylmethyl substitution might significantly enhance the activity. Compound 8a exhibited the highest inhibitory potency against COL1A1, and its inhibition activity against COL1A1 was further confirmed on both the mRNA and protein levels. It also effectively inhibited the expression of α smooth muscle actin (α-SMA), fibronectin and transforming growth factor β1 (TGFβ1), indicating an extensive inhibitory effect on the expression of fibrogenic genes. The primary mechanism study indicated that it might take action via the Integrin/FAK/PI3K/Akt signaling pathway. The results provided powerful information for further structure optimization, and compound 8a was selected as a novel anti-fibrogenic lead for further investigation.
- Bao, Yunyang,Pang, Yudong,Tang, Sheng,Niu, Tianyun,Guo, Zhihao,He, Hongwei,Li, Yinghong,Song, Danqing
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- Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease
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Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors (Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC50 = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
- Wi?ckowska, Anna,Wichur, Tomasz,Godyń, Justyna,Bucki, Adam,Marcinkowska, Monika,Siwek, Agata,Wi?ckowski, Krzysztof,Zar?ba, Paula,Knez, Damijan,G?uch-Lutwin, Monika,Kazek, Grzegorz,Latacz, Gniewomir,Mika, Kamil,Ko?aczkowski, Marcin,Korabecny, Jan,Soukup, Ondrej,Benkova, Marketa,Kie?-Kononowicz, Katarzyna,Gobec, Stanislav,Malawska, Barbara
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p. 1195 - 1214
(2018/05/25)
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- S-substituted derivatives of 1,2,4-triazol-3-thiol as new drug candidates for type II diabetes
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The therapeutic applications of 1,2,4-triazoles motivated us to synthesize some new derivatives. Two series of S -substituted derivatives (8a–8j, 12a–12i) of 5- (1-[(4-chlorophenyl)sulfonyl]-3-piperidinyl )-4-phenyl-4 H -1,2,4-triazol-3-thiol (6) have been synthesized and evaluated for their biological potential. Using 4-chlorobenzene sulfonyl chloride (1) and ethyl piperidine-3-carboxylate (2), ethyl 1-[(4-chlorophenyl)sulfonyl]piperidine-3-carboxylate (3) was synthesized and converted into 3,4,5-trisubstituted 1,2,4-triazole (6) through formation of the corresponding carbohydrazide (4) and hydrazinecarbothioamide (5). Compound 6 was transformed into 8a–8j by alkyl halides (7a–7j) and into 12a–12i by N -aralkyl/aryl-2-bromoacetamides (11a–11i) in an aprotic solvent. The electrophiles, 11a–11i, were synthesized by gearing up N -substituted aralkyl/aryl amines (10a–10i) with 2-bromoacetyl bromide (9) under dynamic pH control by aqueous sodium carbonate. Structures were elucidated through the spectral techniques of IR, EIMS, 1 H NMR, and 13 C NMR. Most of the synthesized derivatives were found to be potent inhibitors of α -glucosidase enzyme and even better than acarbose. Acarbose is a reference standard and is a commercially available α -glucosidase inhibitor to treat patients with type II diabetes. The low hemolytic activity also emphasized the potential of the synthesized compounds as new drug candidates.
- Ur-Rehman, Aziz,Nafeesa, Khadija,Athar Abbasi, Muhammad,Zahra Siddiqui, Sabahat,Rasool, Shahid,Adnan Ali Shah, Syed,Ashraf, Muhammad,Lodhi, Muhammad Arif,Khan, Farman Ali,Jahan, Bakhat
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p. 652 - 671
(2018/06/07)
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- Synthesis, biological evaluation, and in silico study of some unique multifunctional 1,2,4-triazole acetamides
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The imperative demand for antibacterial agents and enzyme inhibitors prompted us to synthesize some new compounds, 6a–6k, bearing multifunctional moieties. The target acetamides were derived from 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (3). The structural analysis was carried out using modern spectroscopic techniques including IR, NMR, and EIMS spectral analysis. The antibacterial activity was screened against five bacterial strains including three gram-negative and two gram-positive ones. Enzyme inhibition was carried out against lipoxygenase enzyme and results were supported by in silico study. The synthesized compounds were proved to be potent antibacterial agents and enzyme inhibitors.
- Sattar, Almas,Ur Rehman, Aziz,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Rasool, Shahid,Khalid, Hira,Lodhi, Muhammad Arif,Khan, Farman Ali
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p. 401 - 417
(2018/06/11)
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- Novel indole derivative and medicine containing the same (by machine translation)
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[A] formation of Amyloid fibrils can be compounds, including therapeutic or prophylactic agent for neurodegenerative disease Amyloid fibrils formation inhibitor compound and of. (I) or its pharmaceutically acceptable compound represented by the formula [a] or a salt or solvate thereof includes the, Amyloid fibrils formation inhibitor. [R1 And R2 Each independently is H, an alkyl group, a cyano group or the like; R3 And R4 Each independently is H, or an alkyl group; R3 And R4 The, joint may form a ring; Ar1 And Ar2 The substituted or unsubstituted heteroaryl group are independently substituted/unsubstituted aryl groups /; X and Y are each independently a single bond, - (=O) - C etc., Z is O or CH2 ; N is an integer of 1 - 3][Drawing] no (by machine translation)
- -
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Paragraph 0097; 0098
(2018/06/30)
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- 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains
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2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
- Pissinate, Kenia,Villela, Anne Drumond,Rodrigues, Valnês,Giacobbo, Bruno Couto,Grams, Estêv?o Silveira,Abbadi, Bruno Lopes,Trindade, Rogério Valim,Roesler Nery, Laura,Bonan, Carla Denise,Back, Davi Fernando,Campos, Maria Martha,Basso, Luiz Augusto,Santos, Diógenes Santiago,Machado, Pablo
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supporting information
p. 235 - 239
(2016/03/22)
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- Design, synthesis and evaluation of novel 19F magnetic resonance sensitive protein tyrosine phosphatase inhibitors
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Fluorine is a highly attractive element for both medicinal chemistry and imaging technologies. To facilitate protein tyrosine phosphatase (PTP)-targeted drug discovery and imaging-guided PTP research on fluorine, several highly potent and 19F MR sensitive PTP inhibitors were discovered through a structure-based focused library strategy.
- Li, Yu,Xia, Guiquan,Guo, Qi,Wu, Li,Chen, Shizhen,Yang, Zhigang,Wang, Wei,Zhang, Zhong-Yin,Zhou, Xin,Jiang, Zhong-Xing
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supporting information
p. 1672 - 1680
(2016/08/24)
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- SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc 1 inhibitors
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A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library. These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex.
- Phummarin, Narisa,Boshoff, Helena I.,Tsang, Patricia S.,Dalton, James,Wiles, Siouxsie,Barry, Clifton E.,Copp, Brent R.
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p. 2122 - 2127
(2016/11/18)
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- Synthesis, characterization and biological evaluation of m-phenetidine derivatives
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Summary: The synthesis of compounds bearing sulfamoyl group and amide linkage is pharmacologically important due to their splendid biological activities. In the presented research work N-(3-ethoxyphenyl)-4-methylbenzenesulfonamide (3) was synthesized by the coupling of m-phenetidine (1) with 4-methylbenzenesulfonyl chloride (2) in basic aqueous media. Compound 3 on reaction with 2-bromo-N-aryl/aralkyl substituted acetamides, 5a-d, synthesized the products, 6a-d. The bromination of compound 3 yielded N-(2,4-dibromo-5-ethoxyphenyl)-4-methylbenzenesulfonamide (7) which on further treatment with different electrophiles, 8a-d yielded compound 9a-d. Enzyme inhibition activities of all the synthesized compounds were evaluated against acetylcholinesterase, butyrylcholinesterase, lipoxygenase, urease, chymotrypsin and tyrosinase enzymes; and found to be the most prominent inhibitor of tyrosinase enzyme.
- Aziz-ur-Rehman,Siddiqa, Asia,Abbasi, Muhammad Athar,Rasool, Shahid,Ashraf, Muhammad,Ismail, Tayaba,Arshad, Samreen,Khalid, Noreen,Khan, Khalid Mohammed
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p. 122 - 130
(2015/05/20)
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- Effect of lanthanide complex structure on cell viability and association
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A systematic study of the effect of hydrophobicity and charge on the cell viability and cell association of lanthanide metal complexes is presented. The terbium luminescent probes feature a macrocyclic polyaminocarboxylate ligand (DOTA) in which the hydrophobicity of the antenna and that of the carboxyamide pendant arms are independently varied. Three sensitizing antennas were investigated in terms of their function in vitro: 2-methoxyisophthalamide (IAM(OMe)), 2-hydroxyisophthalamide (IAM), and 6-methylphenanthridine (Phen). Of these complexes, Tb-DOTA-IAM exhibited the highest quantum yield, although the higher cell viability and more facile synthesis of the structurally related Tb-DOTA-IAM(OMe) platform renders it more attractive. Further modification of this latter core structure with carboxyamide arms featuring hydrophobic benzyl, hexyl, and trifluoro groups as well as hydrophilic amino acid based moieties generated a family of complexes that exhibit high cell viability (ED 50 > 300 μM) regardless of the lipophilicity or the overall complex charge. Only the hexyl-substituted complex reduced cell viability to 60% in the presence of 100 μM complex. Additionally, cellular association was investigated by ICP-MS and fluorescence microscopy. Surprisingly, the hydrophobic moieties did not increase cell association in comparison to the hydrophilic amino acid derivatives. It is thus postulated that the hydrophilic nature of the 2-methoxyisophthalamide antenna (IAM(OMe)) disfavors the cellular association of these complexes. As such, responsive luminescent probes based on this scaffold would be appropriate for the detection of extracellular species.
- Peterson, Katie L.,Dang, Jonathan V.,Weitz, Evan A.,Lewandowski, Cutler,Pierre, Valerie C.
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supporting information
p. 6013 - 6021
(2014/07/07)
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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 and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B-NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B-NS3 protease inhibitor with a 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor (1a24, IC50=3.4±0.2μM) of the WNV NS2B-NS3 protease. Molecular docking of 1a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease.
- Samanta, Sanjay,Lim, Ting Liang,Lam, Yulin
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supporting information
p. 994 - 1001
(2013/07/27)
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- α-Aminoamides as ligands in Goldberg amidations
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α-Aminoamides are shown to be useful as ligands in Goldberg amidations. A number of α-aminoamides are examined and the importance of substitution on the α-aminoamides is explored. Acetamide is focused on as the nucleophilic coupling partner due to its low cost, stability and convenience as a protecting group. The initial substrate scope for these catalysts is explored and includes electronically activated and deactivated aryl bromides, however o-substituted aryl bromides are problematic.
- Mitra, Aurpon W.,Hansen, Marvin M.,Laurila, Michael E.,Kolis, Stanley P.,Martinelli, Joseph R.
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supporting information
p. 6580 - 6583
(2013/11/19)
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- Ru(II)-Pheox catalyzed N-H insertion reaction of diazoacetamides: Synthesis of N-substituted α-aminoamides
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An efficient protocol for the preparation of α-aminoamides was developed via the Ru(II)-dm-Pheox catalyzed N-H insertion reaction of various diazoacetamides with several amines, including aniline. This catalytic N-H insertion reaction was also applied to the synthesis of 2-(2-methylquinolin-4- ylamino)-N-phenylacetamide, a potential antileishmanial agent.
- Chanthamath, Soda,Thongjareun, Songkharm,Shibatomi, Kazutaka,Iwasa, Seiji
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supporting information; experimental part
p. 4862 - 4865
(2012/09/08)
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- The design and synthesis of 1,4-substituted piperazine derivatives as triple reuptake inhibitors
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Novel 1,4-substituted piperazine derivatives 5, Series A and B were designed by fragment analysis and molecular modification of 4 selected piperazine-containing compounds which possess antidepressant activity. We synthesized new 39 analogues of Series A and 10 compounds of Series B, respectively. The antidepressant screening against DA, NE, and serotonin neurotransmitter uptake inhibition was carried out using the Neurotransmitter Transporter Uptake Assay Kit. The compounds in Series B showed relatively higher reuptake inhibitory activity for SERT, NET, and DAT than those in Series A. The length of spacer between the central piperazine core and the terminal phenyl ring substituted at the piperazine ring in Series B seems to exert an important role in the activity.
- Han, Minsoo,Han, Younghue,Song, Chiman,Hahn, Hoh-Gyu
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p. 2597 - 2602
(2012/10/29)
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- New Potent Bisubstrate Inhibitors of Histone Acetyltransferase p300: Design, Synthesis and Biological Evaluation
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Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.
- Kwie, Franciane Ho A.,Briet, Martine,Soupaya, David,Hoffmann, Pascal,Maturano, Marie,Rodriguez, Frederic,Blonski, Casimir,Lherbet, Christian,Baudoin-Dehoux, Cecile
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scheme or table
p. 86 - 92
(2011/09/15)
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- Versatile access to 2-aminocyclobutene-1-carboxylic acid derivatives and their incorporation into small peptides
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Under a newly developed set of mild conditions [EtN(iPr)2, LiI, DMF, 20 °C, 3 d], methyl 2-chloro-2-cyclopropylideneacetate (1) smoothly undergoes Michael addition of various benzylamines (4 examples) with ensuing ring enlargement and elimination to give in very good yields (81-99%) the correspondingly substituted methyl 2-(benz-ylammojcyclobutenecarboxylates 3a-d, which were subsequently converted into the N-Boc-protected derivatives 4a-d. After hydrolysis of the esters, the free β-amino acids 5a, b were cleanly condensed with the methyl esters of glycine, (S)-proline, (S)-phenylglycine and (S)-tryptophan to give the dipeptides 6a-8a, 9b in 58-89% yield. The cyclic dipeptides 15e,f, consisting of a 2-aminocyclobutenecarboxylic acid and a glycine fragment, were obtained in 38 and 45 % yield, respectively, upon treatment of the spirocyclopropanated chlorohexahydrodiazepinediones 10e,f with sodium cyanide in DMSO at elevated temperatures. Palladium-catalyzed hydrogenation of 4a afforded, methyl N-Boc-2-aminocyclobutanecarboxylate 19 as a mixture of cis and trons isomers.
- De Meijere, Armin,Limbach, Michael,Janssen, Andre,Lygin, Alexander,Korotkov, Vadim S.
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body text
p. 3665 - 3671
(2010/08/22)
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- Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
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The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.
- Zhang, Xian,He, Yantao,Liu, Sijiu,Yu, Zhihong,Jiang, Zhong-Xing,Yang, Zhenyun,Dong, Yuanshu,Nabinger, Sarah C.,Wu, Li,Gunawan, Andrea M.,Wang, Lina,Chan, Rebecca J.,Zhang, Zhong-Yin
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experimental part
p. 2482 - 2493
(2010/09/03)
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- Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.
- Zhou, Bo,He, Yantao,Zhang, Xian,Xu, Jie,Luo, Yong,Wang, Yuehong,Franzblau, Scott G.,Yang, Zhenyun,Chan, Rebecca J.,Liu, Yan,Zheng, Jianyu,Zhang, Zhong-Yin
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scheme or table
p. 4573 - 4578
(2010/10/03)
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- Delineating origins of stereocontrol in asymmetric Pd-catalyzed α-hydroxylation of 1,3-ketoesters
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Systematic studies of reaction conditions and subsequent optimization led to the identification of important parameters for stereoselectivity in the asymmetric α-hydroxylation reaction of 1,3-ketoesters. Enantioselectivities of up to 98% can be achieved for cyclic substrates and 88% for acyclic ketoesters. Subsequently, the combination of cyclic/acyclic ketoester, catalyst, and oxidant was found to have a profound effect on reaction rates and turnover-limiting steps. The stereochemistry of the reaction contradicts that observed for other similar electrophilic substitution reactions. This was rationalized by transition-state modeling, which revealed a number of cooperative weak interactions between oxidant, ligand, and counterion, together with C-H/π interactions that cumulatively account for the unusual stereoselectivity.
- Smith, Alexander M. R.,Rzepa, Henry S.,White, Andrew J. P.,Billen, Denis,Hii, King Kuok
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supporting information; experimental part
p. 3085 - 3096
(2010/07/17)
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- Structure-activity relationships of 9-substituted-9-dihydroerythromycin- based motilin agonists: Optimizing for potency and safety
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A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties. 2009 American Chemical Society.
- Shaw, Simon J.,Chen, Yue,Zheng, Hao,Fu, Hong,Burlingame, Mark A.,Marquez, Saul,Li, Yong,Claypool, Mark,Carreras, Christopher W.,Crumb, William,Hardy, Dwight J.,Myles, David C.,Liu, Yaoquan
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supporting information; experimental part
p. 6851 - 6859
(2010/04/04)
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- Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus
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The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
- Xie, Hui,Ng, Danny,Savinov, Sergey N.,Dey, Barna,Kwong, Peter D.,Wyatt, Richard,Smith III, Amos B.,Hendrickson, Wayne A.
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p. 4898 - 4908
(2008/03/11)
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- Regioselective alkylation of 3,4-dihydro-2H-pyran by xanthate-mediated free radical nonchain process
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An intermolecular xanthate-mediated free radical nonchain addition reaction is introduced for the regioselective alkylation of 3,4-dihydro-2H-pyran. Additionally, we observed that the free radical nonchain reaction depends on the nature of the radical precursor.
- Torres-Murro, Jaime,Quintero, Leticia,Sartillo-Piscil, Fernando
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p. 7691 - 7694
(2007/10/03)
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- One-pot conversion of t-butyl carbamates to amides with acyl halide-methanol mixtures
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Acyl halide-methanol mixtures are efficient reagents for the one-pot transformation of t-butyl carbamates into amides. This transformation can be carried out in the presence of a benzyloxycarbonyl group.
- Nazih, Abdesslame,Heissler, Denis
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p. 203 - 206
(2007/10/03)
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- Peptide-small molecule hybrids via orthogonal deprotection-chemoselective conjugation to cysteine-anchored scaffolds. A model study
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(formula presented) The feasibility of an orthogonal deprotection - conjugation protocol, holding the promise of libraries of functionally diverse chemical probes attached to cysteine-anchored peptide scaffolds, has been explored with a model system. The
- Smith III, Amos B.,Savinov, Sergey N.,Manjappara, Uma V.,Chaiken, Irwin M.
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p. 4041 - 4044
(2007/10/03)
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- Indium-mediated reductive dehalogenation of α-halocarbonyl compounds in water
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Reactions of various α-halocarbonyl compounds 1 with indium in the presence of a catalytic amount of sodium dodecyl sulfate in water were performed to afford the corresponding parent carbonyl compounds 2 in excellent yields. The Royal Society of Chemistry 2000.
- Park, Leeyoung,Keum, Gyochang,Kang, Soon Bang,Kim, Kwan Soo,Kim, Youseung
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p. 4462 - 4463
(2007/10/03)
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- Staudinger ligation: a peptide from a thioester and azide.
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[reaction: see text] The technique of native chemical ligation enables the total chemical synthesis of proteins. This method is limited, however, by an absolute requirement for a cysteine residue at the ligation juncture. Here, this restriction is overcome with a new chemical ligation method in which a phosphinobenzenethiol is used to link a thioester and azide. The product is an amide with no residual atoms.
- Nilsson,Kiessling,Raines
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p. 1939 - 1941
(2007/10/03)
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- Reactions of a new family of amide derivatives of phenanthridinium azomethine ylides with dipolarophiles
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Reaction of a series of N-alkyl- and N,N-dialkylbromoacetamides 1a-1e with phenanthridine afforded quaternary phenanthridinium salts 2a-2e. These compounds treated with triethylamine form azomethine ylides which undergo a cycloaddition reaction with activated C=C bond, giving 3-(N-alkylcarbamoyl)-1,2,3,12b-tetrahydropyrrolo[1,2-f]phenanthridines 3a-3e, 4c, 5c, 6c or 3-(N-alkylcarbamoyl)-2,3-dihydropyrrolo[1,2-f]phenanthridine 7c. Their stereochemistry was studied by NMR spectroscopy. The best results were obtained with fumaronitrile as a dipolarophile. It has been found that the ylides react in syn conformations but if 1-adamantyl moiety is bound to the ylide, it reacts in anti conformation, too. The azomethine ylides show a very poor reactivity towards dimethyl fumarate or dimethyl maleate. Yet we could prepare products for ylide bearing 1-adamantyl group.
- Travnicek, Martin,Pospisil, Jiri,Potacek, Milan
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p. 1993 - 2006
(2007/10/03)
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- Tetraethylammonium hydrogen carbonate in organic synthesis: Synthesis of oxazolidine-2,4-diones
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Oxazolidine-2,4-diones were synthesised by tetraethylammonium hydrogen (TEAHC) promoted carboxylation of secondary carboxamides bearing a leaving group at the α-position. Several oxazolidine-2,4-diones, including clinically used malidone, have been prepared in moderate to excellent yields as a results of a formal proton extraction-carboxylation- intramolecular S(N)2 one-pot sequence.
- Cesa, Stefania,Mucciante, Vittoria,Rossi, Leucio
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p. 193 - 200
(2007/10/03)
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- (+)-cis-N-ethyleneamino-N-normetazocine derivatives. Novel and selective sigma ligands with antagonist properties.
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A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-subs
- Ronsisvalle,Marrazzo,Prezzavento,Pasquinucci,Vittorio,Pittala,Pappalardo,Cacciaguerra,Spampinato
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p. 1574 - 1580
(2007/10/03)
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