Halogen-substituted Derivatives Research Articles

Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment

Keeping in view the pharmacological properties of indolinones as promising scaffold as kinase inhibitors, herein, a novel series of 3-hydrazonoindolin-2-one derivatives bearing 3-hydroxy-4-pyridinone moiety were synthesized, studied by molecular docking, and fully characterized by spectroscopic techniques. All the prepared compounds were evaluated for their cytotoxicity attributes against a panel of tumor cell lines, including non-small cell lung cancer (A549), breast carcinoma (MCF-7), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). They displayed moderate to promising antiproliferative effects toward A549 and MCF-7 cells but remarkable results against AML and CML. Especially, compound 10k was found to be more potent against AML (EC50 = 0.69 μM) compare to the other halogen-substituted derivatives. FMS-like tyrosine kinase 3 (FLT3) is known to be expressed in AML cancer cells. The molecular docking studies demonstrated that our prepared compounds were potentially bound to AML active site through essential H-bond and other vital interactions with critical binding residues.

Experimental and Computational Studies on Structure and Energetic Properties of Halogen Derivatives of 2-Deoxy-D-Glucose.

The results of structural studies on a series of halogen-substituted derivatives of 2-deoxy-D-glucose (2-DG) are reported. 2-DG is an inhibitor of glycolysis, a metabolic pathway crucial for cancer cell proliferation and viral replication in host cells, and interferes with D-glucose and D-mannose metabolism. Thus, 2-DG and its derivatives are considered as potential anticancer and antiviral drugs. X-ray crystallography shows that a halogen atom present at the C2 position in the pyranose ring does not significantly affect its conformation. However, it has a noticeable effect on the crystal structure. Fluorine derivatives exist as a dense 3D framework isostructural with the parent compound, while Cl- and I-derivatives form layered structures. Analysis of the Hirshfeld surface shows formation of hydrogen bonds involving the halogen, yet no indication for the existence of halogen bonds. Density functional theory (DFT) periodic calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings. NMR studies in the solution show that most of the compounds do not display significant differences in their anomeric equilibria, and that pyranose ring puckering is similar to the crystalline state. For 2-deoxy-2-fluoro-D-glucose (2-FG), electrostatic interaction energies between the ligand and protein for several existing structures of pyranose 2-oxidase were also computed. These interactions mostly involve acidic residues of the protein; single amino-acid substitutions have only a minor impact on binding. These studies provide a better understanding of the structural chemistry of halogen-substituted carbohydrates as well as their intermolecular interactions with proteins determining their distinct biological activity.

Theoretical study of the effect on halogen-substitution and molecular torsion angle on transport properties of π Stack Hexabenzoperylenes and its derivatives

The halogen-substituted derivatives and the hexabenzoperylenes in organic semiconductors are theoretically studied using density functional theory. The effects of halogen-substitution on intramolecular energy-level transition and intermolecular stacking patterns are discussed by studying the charge transfer and spectral characteristics. The results show that halogen atom can effectively lower the frontier molecule orbitals energy and enhance the molecular stability. Not only the plane characteristics of the molecular structure been controlled, but also the semiconductors can be converted from p-type to n-type by changing the number and position of halogen-substituted atoms. The studies reveal that the molecular torsion angle can been used to effectively predict the transport level of molecules, and the halogen-substitution play an important part in the photochemical properties of molecules.

Thermal induced spin transition in a series of iron(II) layered inorganic-organic solids. Role of the intermolecular interactions in the interlayer region

The understanding of the factors that determine the spin crossover phenomenon in transition metal-containing solids is a relevant subject in order to design new materials with tunable physical and functional properties based on such spin transition. This is a process that has been studied for decades but even not fully understood in terms of the electronic and structural features that could determine its control and tuning for a given potential application. In this contribution, we shed light in that sense, through an evaluation of the iron atom coordination environment from Raman, Mössbauer, XPS, and structural data for a series formed by the intercalation of the pyridine (Py) molecule (L) and its halogen-substituted derivatives (3X-py) between neighboring layers of iron(II) tetracyanonickellate, Fe(L)2[Ni(CN)4]. In their structure, the organic molecule (L) is found occupying the axial coordination sites for the iron atom. The halogen atom determines both, the relative orientation of neighboring molecules in the interlayer region and the dominant intermolecular forces, through dispersive interactions. When such interaction generates a local distortion for the iron atom coordination environment, the thermal induced spin transition is inhibited. This is properly supported by the herein discussed experimental data.

Halogen-Substituted Derivatives of Dictyostelium Differentiation-Inducing Factor-1 Suppress Serum-Induced Cell Migration of Human Breast Cancer MDA-MB-231 Cells in Vitro.

Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-inducing factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 μM) with negligible effects on cell proliferation (IC50, >20 μM). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 μM, respectively, without affecting cell proliferation (IC50, >20 μM). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.

An insight into intramolecular blue-shifting C[sbnd]H⋯π hydrogen bonds in 1,3-hexadien-5-yne and its halogen-substituted derivatives

The blue-shifting intramolecular CH⋯π hydrogen bonds (H-bonds) in conformer I of 1,3-hexadien-5-yne (13HD5Y) and its halogen-substituted derivatives are explored by theoretical calculations. The geometric analysis indicates that the CH bond in conformer I is shortened in comparison with the non-interacting CH bond, accompanied by the blue-shifts of the CH stretching frequency. The formation of H-bonds is verified by the atoms-in-molecules and noncovalent interaction analysis. The H-bond energies are estimated to be −0.5∼−2.2 kcal·mol−1 by isodesmic reaction method at MP2/aug-cc-pVTZ level, which agree with the trends predicted by the geometrical and topological parameters. The results of the natural bond orbital analysis indicate that the origin of the blue-shifting H-bond may be due to the weak π(CC) → σ*(CH) hyperconjugation interaction and the concomitant increasing in the s-character and polarization of CH bond. This research provides a rare theoretical evidence to identify an intramolecular blue-shifting CH⋯π H-bond system.

Peculiarities of the reactions of a,b-unsaturated g-bromoketones with hydrazine derivatives

The reaction result of a,b-unsaturated g-bromoketones with hydrazines depends on the structure of the reagents. Reaction with hydrazine hydrate leads to the mixture of 3,5- di(R)pyridazine, 3,6-di(R)pyridazine and 2,4-di(R)-1H-pyrrol-1-amine derivatives. The formation of three types of products is due to the structure of the unsaturated aliphatic ketone. Two competing reaction schemes of ketones with hydrazines are considered, which include condensation or Michael-type addition in the first stage. The main products of the reactions of halogen-substituted derivatives of g-bromodipnone with arylhydrazines are 1,3,5-triaryl-1,6-dihydropyridazines, which easily form aromatic salts under reaction conditions (when heated in EtOH).

Modeling of the structure and IR spectra of boron difluoride acetylacetonate and its halogen-substituted derivatives

The infrared spectra of the complexes of boron difluoride acetylacetonate and its halogen-substituted derivatives F2B(aaX) (X = H, Cl, Br, I) in the crystalline state are studied. The substituent effect on the geometry and force field of molecules is revealed from DFT/B3LYP quantum chemical calculations with the 6-311G(d,p) basis set. The detailed assignment of IR absorption bands is performed based on the calculations of normal modes (NMs) and the potential energy distribution (PED). The bands most sensitive to the substituent nature belong to vibrations with prevalent involvement of ring CC and CO bonds and some low-frequency noncharacteristic NMs involving the Х atom. In support of the single crystal XRD data, intermolecular interactions have the strongest effect on the characteristic bands of the BF2 moiety in the ranges 1280-1220 cm–1 and 875-835 cm–1; the sequences of IR band frequency shifts in a series of substituents corresponding to these interactions are reported.

Halogen Bonds Formed between Substituted Imidazoliums and N Bases of Varying N-Hybridization.

Heterodimers are constructed containing imidazolium and its halogen-substituted derivatives as Lewis acid. N in its sp3, sp2 and sp hybridizations is taken as the electron-donating base. The halogen bond is strengthened in the Cl < Br < I order, with the H-bond generally similar in magnitude to the Br-bond. Methyl substitution on the N electron donor enhances the binding energy. Very little perturbation arises if the imidazolium is attached to a phenyl ring. The energetics are not sensitive to the hybridization of the N atom. More regular patterns appear in the individual phenomena. Charge transfer diminishes uniformly on going from amine to imine to nitrile, a pattern that is echoed by the elongation of the C-Z (Z=H, Cl, Br, I) bond in the Lewis acid. These trends are also evident in the Atoms in Molecules topography of the electron density. Molecular electrostatic potentials are not entirely consistent with energetics. Although I of the Lewis acid engages in a stronger bond than does H, it is the potential of the latter which is much more positive. The minimum on the potential of the base is most negative for the nitrile even though acetonitrile does not form the strongest bonds. Placing the systems in dichloromethane solvent reduces the binding energies but leaves intact most of the trends observed in vacuo; the same can be said of ∆G in solution.

Influence of the Halogenated Substituent on Charge Transfer Mobility of Aniline Tetramer and Derivatives: Remarkable Anisotropic Mobilities

The halogen-substituted derivatives and the parent aniline tetramer as organic semiconductors have been theoretically investigated with a focus on the electronic properties and charge transport properties through density functional theory and Marcus–Hush theory methods. The study on the transport properties of holes and electrons can obtain insight into the effect of halogenation substitution on injection of charge carriers and transport character. The equilibrium geometries, reorganization energies, frontier molecular orbitals, intermolecular electronic couplings, electrostatic potential isosurfaces, and angular resolution anisotropic mobilities were calculated. The calculated results revealed that perfluorination and perchlorination can induce stronger structure relaxation and effectively lower the highest occupied molecular orbital and lowest unoccupied molecular orbital levels. The angle dependence mobilities of the three crystals show remarkable anisotropic character. The carrier mobility curves for both electron and hole transport of the parent aniline tetramer and halogen-substituted derivatives all show a remarkable anisotropic feature. Furthermore, the ANIH and ANICl crystals show higher electron-transfer mobilities than hole-transfer mobilities and, hence, perform better as an n-type organic semiconductor. The ANIH crystal possesses a low reorganization energy combined with a high electronic coupling and electron-transfer mobility, which indicates that the ANIH crystal might be a more ideal candidate as an n-type organic semiconductor material.

Halogen-substituted catechol bisphosphates are potent and selective inhibitors of the transcription factor STAT5b

The transcription factor STAT5b is an antitumor target. Recently, we presented the small molecules Stafib-1 and Stafib-2 as potent, selective inhibitors of the STAT5b SH2 domain. Here we report that halogen substitutions on the terminal phenyl ring of Stafib-1 and a close derivative are tolerated and specificity over the STAT5a SH2 domain is maintained, albeit with a slight reduction in activity. Our data demonstrate that the synthetic methodology used for generating Stafib-1 and Stafib-2 can be utilized to synthesize a small library of halogen-substituted derivatives, and extend the panel of catechol bisphosphate-based submicromolar and selective STAT5b inhibitors.

NXY halogen bonds. Comparison with NHY H-bonds and CXY halogen bonds.

Quantum calculations examine how the NHY H-bond compares to the equivalent NXY halogen bond, as well as to comparable CH/CX donors. Succinimide and saccharin, and their corresponding halogen-substituted derivatives, are chosen as the prototype NH/NX donors, paired with a wide range of electron donor molecules. The NHY H-bond is weakened if the bridging H is replaced by Cl, and strengthened by I; a Br halogen bond is roughly comparable to a H-bond. The lone pairs of the partner molecule are stronger electron donors than are π-systems. Whereas Coulombic forces represent the largest fraction of the attractive force in the H-bonds, induction energy is magnified in the halogen bonds, surpassing electrostatics in several cases. Mutation of NH/NX to CH/CX weakens the binding energy to roughly half its original value, while also lengthening the intermolecular distances by 0.3-0.8 Å.

Spectral and Electroluminescent Properties of Binuclear Zinc Complexes with Halogen-Substituted Derivatives of 1,2,4-Triazole

Spectral properties of binuclear zinc complexes in chloroform solutions and polyvinylcarbazole (PVC) films are investigated. It is demonstrated that incorporation of a halogen atom (chlorine or bromine) in a ligand benzene ring leads to a small shift of the spectrum toward the red region and a reduction of the fluorescence quantum yield. The fluorescence and phosphorescence spectra at T = 77K are investigated. The fluorescence undergoes a blue shift of about 30 nm and multiply increases in the intensity, and the phosphorescence is observed at 540–580 nm. The phosphorescence lifetime is estimated. The electroluminescent properties of metal complexes in structures with thermal vacuum spin coating of complexes and in PVC films are investigated.

Enthalpies of Vaporization and Sublimation of the Halogen-Substituted Aromatic Hydrocarbons at 298.15 K: Application of Solution Calorimetry Approach

Recently, the solution calorimetry has been shown to be a valuable tool for the indirect determination of vaporization or sublimation enthalpies of low volatile organic compounds. In this work we studied 16 halogen-substituted derivatives of benzene, naphthalene, biphenyl, and anthracene using a new solution calorimetry based approach. Enthalpies of solution at infinite dilution in benzene as well as molar refractions for the chlorine-, bromine-, and iodine-substituted aromatics were measured at 298.15 K. Vaporization and sublimation enthalpies of these compounds at 298.15 K were indirectly derived from the solution calorimetry data. In order to verify results obtained by using solution calorimetry, vaporization/sublimation enthalpies for 1,2-, 1,3-, 1,4-dibromobenzenes, 4-bromobiphenyl, and 4,4′-dibromobiphenyl were additionally measured by using the well established transpiration method. Experimental data available in the literature were collected and evaluated in this work for the sake of comparison wi...

Revealing the specific solute–solvent interactions via the measurements of the NMR spin–spin coupling constants

The solvent induced changes of one-bond spin–spin coupling constants (SSCCs) are investigated for a set of substituted methanes in solvents with various ε dielectric constants. Solute–solvent systems with varying types of ε-dependences for the solute SSCCs are outlined. Aliphatic hydrocarbon solvents and their halogen-substituted derivatives comprise the subset, where the SSCC is linearly dependent on the solvent reaction field, f(ε)=2(ε−1)/(2ε+1), hence indicating the absence of specific solute–solvent interactions. In such solvents, SSCCs depend only on bulk dielectric properties of the medium, and, the magnitudes of the solvent sensitivities of SSCCs are fully determined by the initial values of “pure” SSCCs that correspond to the isolated solute molecules. The solvents involved in the second subset have a relatively chaotic distribution of the SSCC/f(ε) relationship, with possible groupings by their chemical nature. There, the conventional linear SSCC/f(ε) dependence is perturbed by additional interactions, such as hydrogen bonding, specific association processes, lone electron pairs, and conjugation.

Mercuration of thiacalix[4]arenes in the cone and 1,3-alternate conformations.

The first mercuration in the thiacalixarene series using thiacalix[4]arenes immobilized in the cone or 1,3-alternate conformations gave a mixture of two monomercurated regioisomers (meta and para) in approx. 4 : 1 and 2 : 1 ratios, respectively. The organomercurial intermediates show unusual solid-state behaviour, as evidenced by the formation of η(6) complexes, and can be easily transformed into halogen-substituted derivatives, so far inaccessible in thiacalixarene chemistry. This paves the way towards the synthesis of inherently chiral thiacalixarene-based receptors with an unusual substitution pattern.

Electronic Structure and Conformation Properties of Halogen -Substituted Acetyl Acrylic Anhydrides, CX3C(O)OC(O)CH═CH2 (X = H, F, or Cl)

Acetyl acrylic anhydride (CH(3)C(O)OC(O)CHCH(2)) and its halogen-substituted derivatives (CF(3)C(O)OC(O)CHCH(2) and CCl(3)C(O)OC(O)CHCH(2)) were prepared by the heterogeneous reaction of gaseous CH(2)═CHC(O)Cl with CX(3)C(O)OAg (X = H, F, or Cl). The molecular conformations and electronic structure of these three compounds were investigated by HeI photoelectron spectroscopy, photoionization mass spectroscopy, FT-IR, and theoretical calculations. They were theoretically predicted to prefer the [ss-c] conformation, with each C═O bond syn with respect to the opposite O-C bond and the C═C bond in cis orientation to the adjacent C═O bond. The experimental first vertical ionization potential for CH(3)C(O)OC(O)CHCH(2), CF(3)C(O)OC(O)CHCH(2), and CCl(3)C(O)OC(O)CHCH(2) was determined to be 10.91, 11.42, and 11.07 eV, respectively. In this study, the rule of the conformation properties of anhydride XC(O)OC(O)Y was improved by analyzing the different conformations of anhydrides with various substitutes.

Structure-based design, synthesis, and molecular modeling studies of 1-(benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives as novel anti-Parkinsonian agents

1-(Benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives were designed and synthesized as our efforts to discover novel anti-Parkinsonian agents with improved pharmacological profile in haloperidol-induced catalepsy and oxidative stress in mice. All of the compounds were found to be active in alleviating haloperidol-induced catalepsy in mice. Furfuryl, 2- and/or 3-methoxy substituted phenyl derivatives emerged as potent agents. With exception of 2-chloro,5-trifluoromethyl-substituted analog, halogen-substituted derivatives exhibited moderate anti-Parkinsonian activity. Biochemical estimations of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) from brain homogenate were carried out to highlight the neuroprotective properties associated with them. Molecular docking studies of these compounds with adenosine A2A receptor exhibited very good binding interactions and warrants further studies to confirm their binding with human A2A receptor for the design and development of potent antagonists. Parameters for Lipinski’s rule of 5 were calculated computationally because pharmacokinetic and metabolic behaviors in the body often are linked to the physical properties of a compound. None of the synthesized compounds violated Lipinski’s rule, making them suitable drug candidate for the treatment of Parkinson’s disease.

ChemInform Abstract: Transformation of the Sydnone Ring into Oxadiazolinones. A Convenient One-Pot Synthesis of 3-Aryl-5-methyl-1,3,4-oxadiazolin-2-ones from 3-Arylsydnones and Their Antimicrobial Activity.

Abstract 3-Arylsydnones ( Ia – u ) have been converted into the corresponding 3-aryl-5-methyl-1,3,4-oxadiazolin-2-ones ( IIIa – u ) by a single-step reaction with bromine in acetic anhydride. In the preliminary screening of all these compounds, the halogen-substituted derivatives have shown antimicrobial activities equal to those of the standard drugs used.

Synthesis of new haloderivatives of benzo[f]quinoline and 4,7-phenanthroline

By condensations of 2-naphthylamine and 6-aminoquinoline with halogen-substituted benzaldehydes, 3-acetylpyridine and acetophenone derivatives new 1,3-diaryl(heteryl)benzo-[f]quinolines and 4,7-phenanthrolines were synthesized containing atoms of fluorine, bromine, and chlorine in the phenyl rings.