Potential Bidentate Research Articles

Molecular Docking, ADMET Study, Synthesis, Characterization and Preliminary Antiproliferative Activity of Potential Histone Deacetylase Inhibitors with Isoxazole as New Zinc Binding Group

Histone acetylation is a highly interesting epigenetic target for drug therapy. Histone deacetylase enzymes (HDACs) are overexpressed in several diseases, including cancers. Most of the clinically used HDAC inhibitors involve hydroxamate group as a zinc-binding group (ZBG). Hydroxamates have a poor pharmacokinetic properties and high toxicity profile. Therefore, developing non-hydroximate HDAC inhibitors is a promising strategy for potency and selectivity enhancement. In this work, we designed new HDAC inhibitors with isoxazole moiety as ZBG using Ligand Designer from Glide (Schrodinger LLC). The cap group and the linker were optimized through trying various aliphatic and aromatic residues. The potential inhibition over HDAC8 for the optimally designed products was virtually evaluated using licensed Schrodinger modelling software. The results showed that the isoxazole has a potential bidentate interaction with HDAC8 active site zinc ion with acceptable fitness. ADMET/tox study performed to predict the pharmacokinetic properties for the final compounds. The final compounds showed a decent estimated drug-like properties. The intermediates and final compounds were successfully synthesized and purified using column chromatography. The chemical structure for intermediates and final compounds were characterized by IR and NMR spectroscopy.

Mechanisms and novel performance of ZrO2/Fe3O4 composite for phosphate recovery from wastewater

In this study, a composite material of Fe3O4 with excellent physical adsorption and ZrO2 with excellent chemical adsorption properties was synthesized to maximize the phosphate recovery efficiency in water. Fe3O4, ZrO2, and Fe3O4/ZrO2 were prepared using co-precipitation and characterized using various surface and structural analysis techniques. Fe3O4 exhibited both physical and chemical adsorption mechanisms, as evidenced by its pseudo-first- and pseudo-second-order kinetics during the adsorption/desorption process, while the dominant adsorption mechanism for ZrO2 was chemical adsorption. The adsorption mechanism of Fe3O4/ZrO2 shows physical adsorption by electrostatic attraction followed by chemical adsorption in which potential bidentate inter-complex and monodentate are formed. From the hydroxyl group analysis, it can be seen that the hydroxyl radicals increased by about 3.5 times or more due to the presence of Fe3O4 on the surface of ZrO2. Overall, the synthesis of Fe3O4/ZrO2 successfully improved the low adsorption performance of Fe3O4 while ameliorating the disadvantages of ZrO2.

Synthesis of β-Thiolated-α-arylated Ketones Enabled by Photoredox and N-Heterocyclic Carbene-Catalyzed Radical Relay of Alkenes with Disulfides and Aldehydes.

β-Thiolated-α-arylated ketones are perversive in bioactive molecules and serve as potential bidentate ligands for catalysis. Herein, a straightforward protocol to access β-thiolated ketones from aldehydes, alkenes, and disulfides enabled by the combination of photocatalysis and N-heterocyclic carbene catalysis is reported. The sequential radical addition to alkenes and subsequent radical-radical coupling cascade process simultaneously forge C-S and C-C bonds. The mild conditions allow for radical relay coupling with a broad functional group tolerance.

Electroreductive C3 Pyridylation of Quinoxalin-2(1H)-ones: An Effective Way to Access Bidentate Nitrogen Ligands

The construction of functional N-containing active biomolecules and bidentate nitrogen ligands by electroreductive pyridylation of N-heteroaromatics is an eye-catching task and challenge. A simple and practical electroreductive-induced C3 pyridylation of quinoxalin-2(1H)-ones with readily available cyanopyridines is reported. More than 36 examples are supplied, and the reaction performed in >95% yield. The present protocol provides a convenient, efficient, and gram-scale synthesis strategy for a series of new types of potential bidentate nitrogen ligands.

Diphosphination of ortho-quinone methide precursors with diphosphines

A fluorine anion-mediated diphosphination of ortho-quinone methide precursors (2-(chloromethyl)silyloxybenzenes) with diphosphines has been developed. The reaction proceeds smoothly under mild conditions (CH2Cl2 solvent, 0 °C) to form the corresponding 2-(phosphinomethyl)oxyphosphinobenzenes, which are potential bidentate ligands in metal catalysis. Additionally, some mechanistic investigations are also performed.

3-Hydroxy-2-Pyrrolidinone as a Potential Bidentate Ligand for in Vivo Chelation of Uranyl with Low Cytotoxicity and Moderate Decorporation Efficacy: A Solution Thermodynamics, Structural Chemistry, and in Vivo Uranyl Removal Survey.

Uranium poses a threat for severe renal and bone damage in vivo. With the rapid development of nuclear industry, it is more urgent than ever to search for potential in vivo uranium chelators. In this work, 3-hydroxy-2-pyrrolidinone (HPD) is investigated as a new potential uranium decorporation ligand. The potentiometric titration measurements were carried out, and the stability constants were determined to be log β110 = 10.5(7), log β120 = 20.7(9), and log β130 = 28.2(4). The species distribution diagram shows that nearly all uranyl is complexed by HPD at pH 7.4 under the defined condition. A single crystal of uranyl and HPD complexes, [(UO2)3O(H2O)3(C4H6NO2)3]·NO3·12H2O (uranyl-HPD), was obtained via an evaporation method. The overall structure of uranyl-HPD is a trimer that consists of three uranyl units and three HPD ligands. The uranyl unit is equatorially coordinated by three oxygen atoms from two HPD agents, one coordinated water molecule, and one μ3-O atom that is shared by three uranyl units. The results of the cytotoxicity assay indicate that the ligand is less toxic than the chelators used clinically (i.e., DTPA-ZnNa3 and 3-hydroxy-1,2-dimethyl-4(1 H)-pyridone (DFP)). The results of the uranium removal assay using the NRK-52E cell show that it could reduce as much as 58% of the uranium content at the cellular level. Furthermore, the in vivo uranium decorporation assays demonstrate that HPD can remove 52% of uranium deposited in the kidney but shows poor uranium removal efficacy in the bone.

Ligand-Enabled, Palladium-Catalyzed β-C(sp3)-H Arylation of Weinreb Amides.

We report the development of Pd(II)-catalyzed C(sp3)-H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp3)-H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development. A pyridinesulfonic acid ligand is designed to accommodate the weak, neutral coordinating property of Weinreb amides via preserving the cationic character of Pd center through zwitterionic assembly of Pd/ligand complexes. DFT studies of the C-H cleavage step indicate that the superior reactivity of 3-pyridinesulfonic acid ligand compared to pyridine, Ac-Gly-OH, and ligandless conditions originates from the stabilization of overall substrate-bound Pd species.

Cu(II), Zn(II), Cd(II) and Hg(II) Complexes of Pantroprazole (PPZH): Synthesis and Characterization

Several metal complexes of pantoprazole, [Cu(PPZ)(H2O)Cl], [Zn(PPZ)2], [Cd(PPZ)2].1.5H2O and [Hg(PPZ)(H2O)Cl] have been synthesized and characterized. Elemental analysis, IR, UV-Visible spectral analysis, magnetic measurement, thermogravimetric analysis, differential scanning calorimetric and cyclic voltammetric techniques were used for their characterization. The lipophilic weak base pantoprazole (PPZ) act as a potential bidentate ligand forming coordination complexes with divalent metal ions through anionic imidazolyl N- and O atom of sulfinyl >S=O group. All complexes possess tetrahedral geometry.
 Dhaka Univ. J. Sci. 66(2): 151-156, 2018 (July)

Small Molecule Microarray Based Discovery of PARP14 Inhibitors.

Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure-activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.

Small Molecule Microarray Based Discovery of PARP14 Inhibitors

AbstractPoly(ADP‐ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small‐molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray‐based strategy for high‐throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20‐fold selectivity over PARP1. Co‐crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure–activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.

Organocatalyst-Induced Multicomponent Reaction: An Efficient Procedure for the Activation of Amides

An efficient organocatalytic route for the activation of amide derivatives is reported. In this transformation, amide derivatives were employed as a potential bidentate nucleophile in a reaction involving isoquinoline and propiolates using tetrabutylphosphonium acetate to form 1,2-dihydroisoquinoline skeletons.

Supramolecular Agent–Simulant Correlations for the Luminescence Based Detection of V‐Series Chemical Warfare Agents with Trivalent Lanthanide Complexes

AbstractSolution spectroscopic investigations into the interactions of eight potential bidentate V‐series organophosphorus chemical warfare agent (OP CWA) simulants with [Eu(phen)2(NO3)3]·2H2O demonstrated that the chemical and structural composition of the secondary binding site within the simulant was of paramount importance. Only simulants containing both phosphoryl/phosphonyl and amine moieties generated analogous spectroscopic behaviours to V‐series OP CWAs seen in previous studies. The results demonstrated that the bidentate chelation mechanism was driven by the phosphoryl/phosphonyl moieties and that the presence of the amine moieties induced a significant secondary dynamic luminescence quenching mechanism. The binding modes of the simulants VO and TEEP to trivalent lanthanides (Eu and La) were further investigated using 1H and 31P NMR spectroscopic titrations and kinetic IR experiments. VO, with both the phosphonyl and amine binding sites was found to be the most appropriate simulant for V‐series OP CWAs in supramolecular studies with trivalent lanthanide ions and we recommend VO for use in supramolecular studies of this type.

Cu(II) complexes of an ionic liquid-based Schiff base [1-{2-(2-hydroxy benzylidene amino) ethyl}-3-methyl­imidazolium]Pf6: Synthesis, characterization and biological activities

Two Cu(II) complexes of an ionic liquid based Schiff base 1-{2-(2-hydroxybenzylideneamino) ethyl}-3-methylimidazolium hexaflurophosphate, were prepared and characterized by different analytical and spectroscopic methods such as elemental analysis, magnetic susceptibility, UV-Vis, IR, NMR and mass spectroscopy. The Schiff base ligand was found to act as a potential bidentate chelating ligand with N, O donor sites and formed 1:2 metal chelates with Cu(II) salts. The synthesized Cu(II) complexes were tested for biological activity.

Synthesis, structural, electrochemical, DNA interaction, antimicrobial and molecular docking studies on dimeric copper(II) complexes involving some potential bidentate ligands

The dimeric copper(II) complexes [Cu2(bpy)2(L1)2(ClO4)2] (1), [Cu2(biim)2(L1)2(ClO4)2] (2), [Cu2(bpy)2(L2)2](ClO4)2 (3) and [Cu2(biim)2(L2)2](ClO4)2 (4) (where bpy=2,2′-bipyridine, biim=2,2′-biimidazole, L1=5-methylsalicylaldehyde and L2=5-bromosalicylic acid) have been synthesized and characterized by IR, UV–Vis, ESR and ESI-mass spectroscopy. The single crystal X-ray diffraction study of complexes 1 and 3 showed that the complexes crystallize in triclinic crystal system with the P1¯ space group. All the complexes showed one quasi-reversible redox wave in the cathodic region (E1pc=−0.83 to −0.90V), assignable to the Cu(II)/Cu(I) redox couple. The binding interaction of the complexes with calf thymus DNA (ctDNA) was investigated by absorption, fluorescence, circular dichroism spectral studies and molecular docking techniques. The copper(II) complexes showed good binding affinity to ctDNA and the intrinsic binding constants obtained from UV–Vis spectroscopic studies are 1.16×105, 3.19×105, 1.82×105 and 3.66×105M−1 for complexes 1–4, respectively. The apparent binding constant obtained from fluorescence spectroscopic studies are 1.37×105, 3.33×105, 2.2×105 and 4.7×105M−1 for the complexes 1–4, respectively. The copper(II) complexes showed efficient oxidative cleavage of plasmid pBR322 DNA in the presence of 3-mercaptopropionic acid (MPA) and the cleavage process was found to proceed by a hydroxyl radical mechanism. The ligands and their Cu(II) complexes were screened for antimicrobial activities and the results indicated that the complexes exhibit significant antimicrobial activity compared to the free ligands.

Novel methylene bridged ethylenediamine-type ligands: Synthesis and spectral characterization

Herein we report the synthesis of two new organic compounds, diisobutyl- and diisopentyl N,N?-methylene-(S,S)-ethylenediamine-N,N?-di-2-(3-cyclohexyl)propanoate. A one-pot procedure was carried out by adding the reducing agent and carbonyl compound into the methanol solution of the parent compounds (iso-butyl and iso-pentyl esters of (S,S)-ethylenediamine-N,N?-di-2-(3-cyclohexyl)propanoic acid) in appropriate stoichiometric ratios. The compounds were fully characterized by infrared, ESI-MS, 1D (1H, 13C) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The spectral data confirm the presence of -CH2- group introduced between nitrogen atoms of the ethylenediamine moiety revealing neutral form of potential bidentate ligand.

Modular Approach to the Synthesis of Polydentate NHC-Ligand Precursors (Benzimidazolium Salts) Containing Axial Chiral 1,1′-Binaphthyl via Pd-Catalyzed N-Arylation of 1,2-Diaminobenzene

A convenient and efficient modular approach to the synthesis of polydentate NHC ligand precursors (benzimidazolium salts) containing axial chiral 1,1′-binaphthyl from 1,2-diaminobenzene and BINOL has been developed. The benzimidazolium salts could be regarded as the potential bidentate, tridentate, and tetradentate NHC ligand precursors.

Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed.

Exploration of 1,2-phenylenediboronic esters as potential bidentate catalysts for organic synthesis

Recently, we described the first inverse electron demand Diels–Alder reaction of 1,2-diazene catalyzed by a bidentate Lewis acid. Herein we investigate 1,2-phenylenediboronic esters as potential catalysts for this transformation offering higher stability and easier handling than the currently used boranthracene derivatives. Different 1,2-phenylenediboronic esters were prepared and their ability to form bidentate coordination complexes with phthalazine was analyzed. Although a 1:1 complex was observed, X-ray analysis revealed binding only in a monodentate fashion.

Coordination complexes of NbX5 (X = F, Cl) with (N,O)- and (O,O)-donor ligands and the first X-ray characterization of a neutral NbF5 adduct

A variety of fairly air-stable complexes were prepared by straightforward reactions of NbX5 (X = F, Cl) with a series of potential bidentate (N,O)- and (O,O)-donor ligands in CH2Cl2. NbF5 reacted with equimolar amounts of 2-[(2,6-diisopropylphenyl)iminomethyl]phenol (dpimpH) and 2-benzoyl-6-hydroxy-6-phenylpentafulvene (bhpfH) to afford the mononuclear complexes NbF5[κ(1)(O)-OC6H4CH=NHC6H3(CHMe2)2], 2, and NbF5[κ(1)(O)-bhpfH], 7, respectively. The 1:1 reactions of NbF5 with salicylaldehyde oxime (saoH2) and 2-phenylaminoethanol gave the hexafluoroniobato salts [NbF4{κ(1)(O)-ON(H)=CHC6H4OH}2][NbF6], 3, and [NbF4{κ(1)(O)-OCH2CH2NH2Ph}2][NbF6], 6, respectively. The syntheses of 2, 3 and 6 are accompanied by oxygen to nitrogen intramolecular H migration, leading to the formation of metal-alkoxide moieties. The parallel chemistry of NbCl5 is characterised by HCl release. The 1:1 reactions with dpimpH, saoH2 and bhpfH yielded, respectively, the ionic complex [NbCl2{κ(1)(N):κ(1)(O)-dpimp}2][NbCl6], 4a, the neutral-dinuclear Nb2Cl7[κ(1)(O)-saoH][κ(2)(O)-sao], 5, and the mononuclear NbCl4[κ(2)(O)-bhpf], 8. The tantalum species [TaCl2{κ(1)(N):κ(1)(O)-dpimp}2][TaCl6], 4b, was prepared from TaCl5/dpimpH. The new products 2-8 were fully characterized by analytical and spectroscopic techniques. Moreover the solid state structures of 2 and 8 were ascertained by X-ray diffraction studies; the structure of 2 exhibits an intramolecular bifurcated N-H···(O,F) hydrogen bond. DFT calculations were carried out in order to predict the lowest energy structures in the distinct cases, showing generally good agreement with the experimental data.

Single Strands versus Ladders: Construction of Skeletal Structure via Coordinating Ability of Anions

The rational construction of aesthetic coordinationpolymeric skeletons by means of selection of basic components suchas the coordination geometry of metal ions, the bonding modeof donating atoms, and weak interactions, for example van der Waals, MM bonds, electrostatic interaction, hydrogen-bonds, and π-π interaction, is a promising issue since the materials have various potential applications such as molecular separation, toxic materials adsorption, gasoline containers, ion exchangers, molecular recognition, and luminescent sensors. 1-6 Various types of intriguing network topologies including chain, 7 ladder, 8 grid, 9 brickwall, 10 honeycomb, 11 diamondoid, 12 rutile, 13 and α-polonium 14 by using numerous multidentate ligands with appropriate spacers have been reported. The spacers are basically important factors because they promise greater possibilities for constructing and fine-tuning novel frameworks owing to their flexibility and conformational freedom. In addition, weak interactions via (counter) anions have emerged as another important factor in the formation of molecular skeleton. 15 Concomitantly, research on anion coordinating ability has become a rapidly expanding field owing to a timely interest from environmental pollution, industrial chemical, biological process, ionic liquids, catalysis, lithium battery, and health related perspectives. 16-21 The characteristics of anions such as negative charge, size, a wide range of geometries, significant solvent effects, and pH dependence play key roles in determining the molecular skeleton and behaviors. 22-24 Of these polyatomic anions, NO2 - , NO3 - , and ClO4 - anionsexist in diverse fields and their bonding modesare quite interesting. 25,26 In this context, research on self-assembly of AgX (X - = NO2 - , NO3 - , and ClO4 - ) with a 1,5-bis(isonicotinoyloxy) naphthalene (L) was accomplished. We report aniondependent 1D molecular skeletons,1D molecular ladders consisting of [Ag2(NO2)2(L)]n and 1D single strands consisting of [Ag(L)]n(X)n (X - = NO3 - and ClO4 - ). The L is a new ligand that may possess characteristic properties such as a potential bidentate, an sp 2 angle around C=O (~120 o ), a malleablelength, conformational nonrigidity, and manageable solubility. Exploitation of naphthalene-based-bipyridyl ligand unit as a linear spacer has remained unexplored. L was prepared by the reaction of 1,5-dihydroxynaphthalene with isonicotinoyl chloride hydrochloride in the presence of triethylamine. L is soluble in chloroform, dichloromethane, tetrahydrofuran, and toluene, but is insoluble in water, methanol, ethanol, acetone, diethyl ether, and nhexane. The slow diffusion of an alcoholic solution of AgX (X - = NO2 - , NO3 - , and ClO4 - ) into an organic solution of L afforded different skeletal adducts, presumably owing to the different coordinating nature of the respective anions, as will be explained in detail (Scheme 1). The reactions were initially conducted in the 1 : 1 molar ratio of the silver(I) ions and L, but the products were not significantly affected by either the molar ratio and the concentrations, indicating that the compounds are thermodynamically favorable species. All the compounds are insoluble in water and common organic solvents but dissociated in acetonitrile, dimethyl sulfoxide, and N,N-dimethyformamide. In addition, these products are air-stable but slowly turned to gray powder under light. Characteristic IR frequencies of NO2 - , NO3 - , and ClO4 - appeared at 1270, 1384, and 1087 cm -1 , respectively. Elemental analyses were consistent with the proposed structures. The crystal structures of [Ag2(NO2)2(L)]n and [Ag(L)]n(X)n (X - =NO3 - and ClO4 - ) were solved. Crystal parameters and procedural information corresponding to data collection and structure refinements are given in Table 1, and selected bond lengths and angles are listed in Table 2. They are centrosymmetric molecules as depicted in Fig. 1. For [Ag2(NO2)2(L)]n, combining AgNO2 and L in a 2 :