18081-89-5Relevant academic research and scientific papers
Synthesis, Pharmacological Characterization, and Structure-Activity Relationships of Noncanonical Selective Agonists for α7 nAChRs
Camacho-Hernandez, Gisela Andrea,Stokes, Clare,Duggan, Brendan M.,Kaczanowska, Katarzyna,Brandao-Araiza, Stefania,Doan, Lisa,Papke, Roger L.,Taylor, Palmer
, p. 10376 - 10390 (2019)
A lack of selectivity of classical agonists for the nicotinic acetylcholine receptors (nAChR) has prompted us to identify and develop a distinct scaffold of α7 nAChR-selective ligands. Noncanonical 2,4,6-substituted pyrimidine analogues were framed around compound 40 for a structure-activity relationship study. The new lead compounds activate selectively the α7 nAChRs with EC50's between 30 and 140 nM in a PNU-120596-dependent, cell-based calcium influx assay. After characterizing the expanded lead landscape, we ranked the compounds for rapid activation using Xenopus oocytes expressing human α7 nAChR with a two-electrode voltage clamp. This approach enabled us to define the molecular determinants governing rapid activation, agonist potency, and desensitization of α7 nAChRs after exposure to pyrimidine analogues, thereby distinguishing this subclass of noncanonical agonists from previously defined types of agonists (agonists, partial agonists, silent agonists, and ago-PAMs). By NMR, we analyzed pKa values for ionization of lead candidates, demonstrating distinctive modes of interaction for this landscape of ligands.
NADH MODEL REDUCTION: BIOMIMETIC SYNTHESIS OF α-AMINO ACIDS FROM α-KETO ACIDS
Shinkai, Seiji,Hamada, Hisatake,Dohyama, Akihiko,Manabe, Osamu
, p. 1661 - 1664 (1980)
Protonated α-imino acids, RC(=NH2+)COOH, were easily reduced to α-amino acids by an acid-stable NADH analoque, 1-benzyl-3-carbamoyl-1,4-dihydroquinoline.This is the first model reaction of NADH-mediated α-amino acid synthesis from α-keto acids.
Activity-Based Sensing of Ascorbate by Using Copper-Mediated Oxidative Bond Cleavage
Yu, Zuo Hang,Reinhardt, Christopher J.,Wong, Thomas Hin-Fung,Tong, Ka Yan,Chan, Jefferson,Au-Yeung, Ho Yu
, p. 8794 - 8800 (2020)
Ascorbate is an important biological reductant and enzyme cofactor. Although direct detection through ascorbate-mediated reduction is possible, this approach suffers from poor selectivity due to the wide range of cellular reducing agents. To overcome this limitation, we leverage reduction potential of ascorbate to mediate a copper-mediated oxidative bond cleavage of ether-caged fluorophores. The copper(II) complexes supported by a {bis(2-pyridylmethyl)}benzylamine or a {bis(2-pyridylmethyl)}(2-methoxybenzyl)amine ligand were identified as an ascorbate responsive unit and their reaction with ascorbate yields a copper-based oxidant that enables rapid benzylic oxidation and the release of an ether-caged dye (coumarin or fluorescein). The copper-mediated bond cleavage is specific to ascorbate and the trigger can be readily derivatized for tuning photophysical properties of the probes. The probes were successfully applied for the fluorometric detection of ascorbate in commercial food samples, human plasma, and serum, and within live cells by using confocal microscopy and flow cytometry.
Syntheses and chromotropic behavior of two halo bridged dinuclear copper(II) complexes containing pyridine-based bidentate ligand
Shirvan, Atie,Golchoubian, Hamid,Bouwman, Elisabeth
, p. 769 - 777 (2019)
Two dinuclear doubly bridged copper(II) complexes [LCu(μ-Cl)Cl]2 (1) and [LCu(μ-Br)Br]2 (2), where L represents N-benzyl(pyridine-2-yl)methaneamine, have been synthesized to investigate their chromotropic behavior. The structures of the complexes were characterized by elemental analyses, various spectroscopic techniques (IR, UV–Vis, and EPR), molar conductance measurements and thermal analysis. The crystal structure of compound 1 indicated both copper(II) centers are located in N2Cl3 environments with distorted square pyramidal geometries, which sharing one base to apex edge. The complexes are chromotropic and their solvatochromism, halochromism, and thermochromism properties were investigated by visible absorption spectroscopy. The solvatochromic properties of the complexes are attributed to structural changes in various solvents. Their halochromism phenomena arise from protonation and deprotonation of coordinated ligands in the pH range of 2.0–10.5, and the reversible thermochromism in DMF and DMSO solutions is triggered by replacing the ligands by solvent molecules.
Calix[4]arenes Linked to Multiple Bidentate N-Donors: Potential Ligands for Synthetic Modeling of Multinuclear Metalloenzymes
Spencer, Douglas J. E.,Johnson, Bryan J.,Johnson, Brian J.,Tolman, William B.
, p. 1391 - 1393 (2002)
(Matrix Presented) A series of calix[4]arenes incorporating three or four bidentate diamines or pyridylamines attached at the upper rim were synthesized via practical protocols. Proof of structure was obtained in one instance by X-ray crystallography. These molecules are designed for general use as ligands for the preparation of multinuclear active site models of metalloenzymes.
Nickel Complexes Bearing N,N,O-Tridentate Salicylaldiminato Ligand: Efficient Catalysts for Imines Formation via Dehydrogenative Coupling of Primary Alcohols with Amines
Han, Zhangang,Hao, Zhiqiang,Lin, Jin,Lu, Guo-Liang,Zhang, Junhua,Zhang, Xiaoying
, p. 3843 - 3853 (2021/11/18)
Treatment of salicylaldiminato ligand L1H-L2H (L1H = 2,4-di-tert-butyl-6-((quinolin-8-ylimino)methyl)phenol; L2H = 2,4-di-tert-butyl-6-(((2-(diethylamino)ethyl)imino)methyl)phenol) with Ni(OAc)2·4H2O in refluxing ethanol afforded nickel complexes [(L1)Ni(OAc)] (1) and [(L2)Ni(OAc)] (2), respectively. Reaction of L3H (L3H = (2,4-di-tert-butyl-6-(((2-(pyridin-2-yl)ethyl)imino)methyl)phenol)) with Ni(OAc)2·4H2O in the presence of excess triethylanmine gave the dual ligands coordinated nickel complex [(L2)2Ni] (3). Complexes 1-3 were well characterized by high-resolution mass spectrometry, infrared spectroscopy, elemental analysis, and X-ray diffraction analysis. All the three Ni(II) complexes exhibited efficient activity and good selectivity in the acceptorless dehydrogenative coupling of alcohols and amines to produce imines and diimines. The present protocol provides an atom-economical and sustainable route for the synthesis of various imine derivatives by employing an earth-abundant nickel salt and easily prepared salicylaldiminato ligands.
Phosphine-Free Manganese Catalyst Enables Selective Transfer Hydrogenation of Nitriles to Primary and Secondary Amines Using Ammonia-Borane
Sarkar, Koushik,Das, Kuhali,Kundu, Abhishek,Adhikari, Debashis,Maji, Biplab
, p. 2786 - 2794 (2021/03/03)
Herein we report the synthesis of primary and secondary amines by nitrile hydrogenation, employing a borrowing hydrogenation strategy. A class of phosphine-free manganese(I) complexes bearing sulfur side arms catalyzed the reaction under mild reaction conditions, where ammonia-borane is used as the source of hydrogen. The synthetic protocol is chemodivergent, as the final product is either primary or secondary amine, which can be controlled by changing the catalyst structure and the polarity of the reaction medium. The significant advantage of this method is that the protocol operates without externally added base or other additives as well as obviates the use of high-pressure dihydrogen gas required for other nitrile hydrogenation reactions. Utilizing this method, a wide variety of primary and symmetric and asymmetric secondary amines were synthesized in high yields. A mechanistic study involving kinetic experiments and high-level DFT computations revealed that both outer-sphere dehydrogenation and inner-sphere hydrogenation were predominantly operative in the catalytic cycle.
Ru(II) complexes containing (2-(pyren-1-ylmethylene)hydrazinyl)benzothiazole: Synthesis, solid-state structure, computational study and catalysis in N-alkylation reactions
Murugan, Kaliyappan,Ojwach, Stephen O.,Saravanan, Kandasamy,Vijayan, Paranthaman,Vijayapritha, Subbarayan,Viswanathamurthi, Periasamy
, (2020/07/27)
Reactions of (2-(pyren-1-ylmethylene)hydrazinyl)benzothiazole (L) with ruthenium(II) prefabricated precursors [RuHCl(CO)(EPh3)3] and [RuH2(CO)(EPh3)3] (E = P or As) afforded new Ru(II) complexes [RuCl(CO)(EPh3)2(L)] and [RuH(CO)(EPh3)2(L)] (E = P or As) (1–4). All the Ru(II) complexes (1–4) were characterized by IR, NMR spectroscopies, ESI-mass spectrometry and elemental analyses. The solid-state structures of Ru(II) complexes (2 and 3) were established by single crystal X-ray analyses and revealed distorted octahedral geometries around the ruthenium(II) ion and mono anionic bidentate N^N coordination mode for hydrazine ligand. The Ru(II) complexes 2 and 3 were also analyzed using Hirshfeld surface analysis and DFT calculations. Moreover, all the complexes (1–4) were utilized in the N-alkylation reactions of amines using alcohol. Complex 3 was found to be highly active towards N-alkylation of different aromatic amines with alcohol.
Zn148 is a modular synthetic metallo-β-lactamase inhibitor that reverses carbapenem resistance in Gram-negative pathogens in vivo
Andresen, Adriana Magalhaes Santos,Bayer, Annette,Carlsen, Trine Josefine Olsen,Finke, Sarah,Heikal, Adam,Huber, Sandra,Kildahl-Andersen, Geir,Lauksund, Silje,Leiros, Hanna-Kirsti S.,Schnaars, Christian,Skagseth, Susann,?strand, Ove Alexander H?gmoen,?kstad, Ole Andreas,Fr?hlich, Christopher,Gj?en, Tor,Rongved, P?l,Samuelsen, ?rjan
supporting information, (2020/06/02)
Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β- lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98percent of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by -30percent, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.
Synthesis and characterization of N,N-chelate manganese complexes and applications in C[sbnd]N coupling reactions
Das, Kuhali,Kumar, Amol,Jana, Akash,Maji, Biplab
, (2019/12/28)
Bidentate NN-ligands have been derived from the reaction between aldehydes and 2-(aminomethyl)pyridine. The treatment of these ligands with Mn(CO)5Br gave complexes that are highly bench stable. The complexes were characterized by various analytical and spectral methods. Single-crystal XRD of complex Mn-2 was performed, which indicates an octahedral geometry around the metal center. The complexes efficiently catalyze the N-alkylation of anilines with alcohols under optimized reaction conditions.
