Design, crystal structure determination, molecular dynamic simulation and MMGBSA calculations of novel p38-alpha MAPK inhibitors for combating Alzheimer's disease

The hallmark of the Alzheimer's disease (AD) is the accumulation of aggregated, misfolded proteins. The cause for this accumulation is increased production of misfolded proteins and impaired clearance of them. Amyloid aggregation and tau hyperphosphorylation are the two proteinopathies which accomplish deprivation of cell and tissue hemostasis during neuropathological process of the AD, as a result of which progressive neuronal degeneration and the loss of cognitive functions. p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in both the events associated with AD: tau protein phosphorylation and inflammation. p38 alpha MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Clinical and preclinical evidence implicates the stress related kinase p38 alpha MAPK as a potential neurotherapeutic target. Drug design of p38 alpha MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here we have carried out the synthesis of phenyl sulfonamide derivatives Sulfo (I) and Sulfo (II). Crystal structures of Sulfo (I) and Sulfo (II) were solved by direct methods using SHELXS-97. Sulfo (I) and Sulfo (II) have R(int)values of 0.0283 and 0.0660, respectively, indicating good quality of crystals and investigated their ability against p38 alpha MAPK. Docking studies revealed that the Sulfo (I) had better binding affinity (-62.24 kcal/mol) as compared to Sulfo (II) and cocrystal having binding affinity of -54.61 kcal/mol and -59.84 kcal/mol, respectively. Molecular dynamics simulation studies of Sulfo (I) and cocrystal of p38 alpha MAPK suggest that during the course of 30 ns simulation run, compound Sulfo (I) attained stability, substantiating the consistency of its binding to p38 alpha MAPK compared to cocrystal. Binding free energy analysis suggests that the compound Sulfo (I) is better than the cocrystal. Thus, this study corroborates the therapeutic potential of synthesized Sulfo (I) in combatting AD

Synthesis, structural characterization and biological properties of cyclometalated iridium(iii) complexes containing 1,2,5]-thiadiazolo-3,4-f]-1,10]-phenanthroline

Two cationic iridium(iii) complexes, Ir(ppy)(2)((tdzp))](+)(1) and Ir(bhq)(2)((tdzp))](+)(2) {ppy = 2-phenylpyridine, bhq = benzoh]quinoline, tdzp = 1,2,5]-thiadiazolo-3,4-f]-1,10]-phenanthroline}, have been synthesized and structurally characterized. The molecular structures of the iridium complexes have been confirmed by single-crystal X-ray structure determination. Extensive hydrogen bonding between lattice water molecules, solvated methanol, and chloride anions is observed in the crystal structure of complex1, which leads to the formation of 1D polymeric cyclic hybrid water-chloride-methanol clusters. The complexes show different photophysical properties in different solvents. The experimental photo-physical properties of the synthesized iridium(iii) complexes match well with the theoretically calculated results obtained by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) studies. The HOMO of complexes1and2is restricted on the iridium and cyclometalated aromatic ligands, while the LUMO, LUMO+1, and LUMO+2 are primarily restricted on the polypyridyl tdzp ligand. The interaction of the complexes with calf thymus DNA (CT-DNA) was investigated by absorption titration and emission titration experiments. Furthermore, the cytotoxicity and cellular localization properties of these complexes towards HeLa cells have been investigated

Investigation of the crystal structures of n-(4-fluorobenzoyl) benzenesulfonamide and n-(4-fluoro-benzoyl)-4-methylbenzenesulfonamide

The title compound, C26H26N2O7, is a thia­midine derivative. Geometric parameters are in the usual ranges. The crystal packing is stabilized by a classical N—H⋯O hydrogen bond, several weak C—H⋯O hydrogen bonds and a π–π stacking inter­action

A fluoro­phore-labelled copper complex: crystal structure, hybrid cyclic water–perchlorate cluster and biological properties

A fluorophore-labelled copper(II) complex, aquabis(dimethylformamide-O)-(perchlorato-O)[2-(quinolin-2-yl)-1,3-oxazolo[4,5-f][1,10]phenanthroline]cop-per(II) perchlorate monohydrate, [Cu(ClO4)(C22H12N4O)(C3H7NO)2(H2O)]-ClO4H2O, has been synthesized and characterized. A cyclic hydrogen-bondedwater–perchlorate anionic cluster,i.e.[(ClO4)2(H2O)2]2, has been identifiedwithin the structure. Each cyclic anionic cluster unit is interconnected byhydrogen bonding to the cation. The cations join into an infinite hydrogen-bonded chain running in the [010] direction. Furthermore, interaction of thecomplex with calf-thymus DNA (CT-DNA) and cellular localization within thecells was explored. Spectroscopic studies indicate that the compound has a goodaffinity for DNA and stains the nucleus of the cells

6,7-Dimethoxy-2,4-diphenylquinoline

In the title structure of the title compound, C23H19NO2, two conformationally similar molecules (A and B) comprise the asymmetric unit. The dihedral angle between phenyl rings bridged by the quinoline moiety are 76.25(8)° in molecule A and 70.39(9)° in molecule B. In the crystal, the independent molecules are connected by C - HO hydrogen bonds and the resulting dimeric aggregates are linked by �-� inter-centroid distance = 3.7370(8)à and C - H� interactions, forming a three-dimensional architecture

Crystal structure of (1E, 1'E)-N, N'-(ethane-1,2-diyl) bis(pyridin-2-yl)methanimine]

The whole molecule of the title compound, C14H14N4, is generated by twofold rotation symmetry. The twofold axis bisects the central -CH2-CH2-bond and the planes of the pyridine rings are inclined to one another by 65.60 (7)degrees. In the crystal, there are no significant intermolecular interactions present

Fluorophore tagged mixed ligand copper(II) complexes: synthesis, structural characterization, protein binding, DNA cleavage and anticancer activity

Two fluorophore tagged copper(II) complexes Cu(phen)(L)(ClO4)(2)] (1) and Cu(bpy)(L)(H2O)(ClO4)](ClO4) (2), (where L=2-amino-1H-benzode]isoquinoline-1,3-(2H)dione (L), phen=1,10-phenanthroline and bpy=2,2 `-bipyridine) have been synthesized and structurally characterized. Structures of the copper complexes 1 and 2 were confirmed by single-crystal X-ray structure determination. The coordination geometry around the copper center of complexes 1 and 2 is distorted octahedral. The plasmid DNA cleavage activity of the complexes has been investigated by agarose gel electrophoresis and the study reveals that both the complexes have high plasmid DNA photo-cleavage activity. The binding interaction ability of the metal complexes with bovine serum albumin (BSA) was investigated using fluorescence spectroscopy. The cytotoxicity of the complexes has been evaluated by MTT (3-4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) assay against A549 (adenocarcinoma human alveolar basal epithelial cells) and MCF-7 (breast cancer cell line) cell lines in comparison with cis-platin. Complexes 1 and 2 have exhibited better cytotoxic activity than cis-platin against A549 and MCF-7 cell lines. The cellular uptake study and localization of the complexes within the cells have been investigated by fluorescence microscopy. The cell staining and flow cytometry experiments suggest that complexes induce an apoptotic mode of cell death

Three closely related (2E,200E)-3,300-(1,4-phenylene)- bis[1-(methoxyphenyl)prop-2-en-1-ones]: supramolecular assemblies in one dimension mediated by hydrogen bonding and C—Hp interactions

In the title compounds, (2E,20E)-3,30-(1,4-phenylene)bis[1-(2-methoxyphenyl)- prop-2-en-1-one], C26H22O4 (I), (2E,20E)-3,30-(1,4-phenylene)bis[1-(3-methoxyphenyl) prop-2-en-1-one], C26H22O4 (II) and (2E,20E)-3,30-(1,4-phenylene)bis[1- (3,4-dimethoxyphenyl)prop-2-en-1-one], C28H26O6 (III), the asymmetric unit consists of a half-molecule, completed by crystallographic inversion symmetry. The dihedral angles between the central and terminal benzene rings are 56.98 (8), 7.74 (7) and 7.73 (7) for (I), (II) and (III), respectively. In the crystal of (I), molecules are linked by pairs of C—H interactions into chains running parallel to [101]. The packing for (II) and (III), features inversion dimers linked by pairs of C—HO hydrogen bonds, forming R2 2(16) and R2 2(14) ring motifs, respectively, as parts of [201] and [101] chains, respectively