Synthesis, computational quantum chemical study, in silico ADMET and molecular docking analysis, in vitro biological evaluation of a novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties as a potential human topoisomerase IIα inhibiting anticancer agent.

Computational quantum chemical study and biological evaluation of a synthesized novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties namely BTPT [2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-6-methoxy-4-(thiophen-2-yl) pyridine] was presented in this study. The crystal structure was determined by SCXRD method. For the title compound BTPT, spectroscopic characterization like 1H NMR, 13C NMR, FTIR, UV-vis were carried out theoretically by computational DFT method and compared with experimental data. Druglikeness parameters of BTPT were found through in silico pharmacological ADMET properties estimation. The molecular docking investigation was performed with human topoisomerase IIα (PDB ID:1ZXM) targeting ATP binding site. In vitro cytotoxicity activity of BTPT/doxorubicin were examined by MTT assay procedure against three human cancer cell lines A549, PC-3, MDAMB-231 with IC50 values of 0.68/0.70, 1.03/0.77 and 0.88/0.98 µM, respectively. Our title compound BTPT reveals notable cytotoxicity against breast cancer cell (MDAMB-231), moderate activity with human lung cancer cell (A-549) and less inhibition with human prostate cancer cell (PC-3) compared to familiar cancer medicine doxorubicin. From the results, BTPT could be observed as a potential candidate for novel anticancer drug development process.

Synthesis, structural elucidation, antioxidant, CT-DNA binding and molecular docking studies of novel chloroquinoline derivatives: Promising antioxidant and anti-diabetic agents.

The synthesized novel chloroquinoline derivatives 1-(2-chloro-4-phenylquinolin-3-yl)ethanone (CPQE), 1-(2,6-dichloro-4-phenylquinolin-3-yl)ethanone (DCPQE), methyl 2,6-dichloro-4-phenylquinoline-3-carboxylate (MDCPQC),methyl 2-chloro-4-methylquinoline-3-carboxylate (MCMQC) were subjected to the elementary analysis like FT-IR, NMR and Mass spectra using GCMS. Also, single crystal X-ray diffraction study was executed for the compound MDCPQC. The crystal packing is stabilized by C-H…π and π-π interactions and also Chlorine-Chlorine short intermolecular contacts generating a three-dimensional supramolecular network. The antioxidant activity reduces high glucose level in the human body and hence the synthesized compounds were subjected for the estimation of antioxidant activity using DPPH method which exhibited good percentage of inhibition in comparison with ascorbic acid, a well-known anti-oxidant. The binding interaction of the chloroquinoline derivatives with calf thymus DNA (CT-DNA) has been explored by fluorescence quenching studies and molecular docking analysis has been employed to confirm the nature of binding. The prediction of pharmacological properties such as drug-likeness, molecular properties like absorption, distribution, metabolism, excretion and toxicity (ADMET) was carried out by computational studies to compare chloroquinoline derivatives with standard drug. Owing to the various potential biological activities of the quinoline compounds, molecular docking studies were also further carried out for the chloroquinoline derivatives, showing that they may act as effective anti-diabetic agents by inhibiting Glycogen Phosphorylase a protein.

Identification of second arginine-glycine-aspartic acid motif of ovine vitronectin as the complement C9 binding site and its implication in bacterial infection.

Vitronectin (Vn), a multifunctional protein of blood and extracellular matrix, interacts with complement C9. This interaction may modulate innate immunity. Details of Vn-C9 interactions are limited. Vn-C9 interactions were assessed by employing a goat homologous system and observing Vn binding to C9 in three different assays. Using recombinant fragments, C9 binding was mapped to the N-terminus of Vn. Site directed mutagenesis was performed to alter the second arginine glycine aspartic acid (RGD) sequence (RGD-2) of Vn. Changing R to G or D to A in RGD-2 caused significant decrease in Vn binding to C9 whereas changing of R to G in the first RGD motif (RGD-1) had no effect on Vn binding to C9. These results imply that the RGD-2 of goat Vn is involved in C9 binding. In a competitive binding assay, the presence of soluble RGD peptide inhibited Vn binding to C9 whereas heparin had no effect. Vn binding to C9 was also evaluated in terms of bacterial pathogenesis. Serum dependent inhibition of Escherichia coli growth was significantly reverted when Vn or its N-fragment were included in the assay. The C-fragment, which did not support C9 binding, also partly nullified serum-dependent inhibition of bacterial growth, probably through other serum component(s).

Crystal structure of [(2S,3R)-3-hy-droxy-3-phenyl-butan-2-yl]pyrrolidinium chloride.

In the title mol-ecular salt, C14H22NO(+)·Cl(-), the pyrrolidinium ring adopts a twisted conformation about one of the N-C bonds. It is oriented at a dihedral angle of 42.0 (1)° with respect to the benzene ring. The torsion angle for the central N-C-C-Car (ar = aromatic) linkage is 163.74 (15)°. In the crystal, the components are linked via N-H⋯Cl and O-H⋯Cl hydrogen bonds, forming zigzig chains along the b-axis direction. These chains are connected along the c axis by very weak C-H⋯π inter-actions, forming a two-dimensional supra-molecular network.

The N-terminal segment of glyceraldehyde-3-phosphate dehydrogenase of Haemonchus contortus interacts with complements C1q and C3.

Haemonchus contortus, an economically important blood-sucking parasite of sheep and goats, survives the harsh host gut environment by secreting a number of proteins referred as excretory/secretory (ES) products. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme, is one of the components of H. contortus ES products. The parasite enzyme binds to complement C3 and inhibits its activity. In this study, the C3-binding activity of the parasite GAPDH was mapped to the N-terminal part of the enzyme by generating defined recombinant fragments of the protein. The N-terminal fragment also trapped complement C1q but not C5 and inhibited complement-mediated lysis of sensitized sheep erythrocytes. Competitive binding assay indicates different binding regions for C1q and C3 proteins. GAPDH stimulated proliferation of goat peripheral blood mononuclear cells in vitro and reacted with the sera from H. contortus-infected animals. However, the fragments of GAPDH did not stimulate cell proliferation nor reacted with the infected animal sera. Furthermore, denatured GAPDH failed to react with the infected animal sera in dot blot suggesting conformation-dependent epitope. These results demonstrate an elegant strategy of the parasite to completely shut down complement activation and identify GAPDH as a promising target for future therapeutic intervention.

Crystal structure of (E)-N-[(2-chloro-6-meth-oxy-quinolin-3-yl)methyl-idene]-9-ethyl-9H-carbazol-3-amine.

In the title compound, C25H20ClN3O, the C=N bond of the central imine group adopts an E conformation. The mean planes through the essentially planar carbazole [maximum deviation = 0.052 (2)Å] and quinoline [maximum deviation = 0.050 (2) Å] ring systems form a dihedral angle of 50.2 (1)°. In the crystal, mol-ecules are linked by C-H⋯π and π-π inter-actions [centroid-centroid distances ranging from 3.635 (2) to 3.739 (2) Å], forming a three-dimensional supra-molecular network.

Crystal structure of (E)-N-(3,3-di-phenyl-allyl-idene)-9-ethyl-9H-carbazol-3-amine.

In the title compound, C29H24N2, the C=N bond of the central imine group adopts an E conformation. The dihedral angles between the mean plane of the essentially planar carbazole ring system [r.m.s. deviation = 0.039 (2) Å] and the two phenyl rings of the 3,3-di-phenyl-allyl-idene unit are 75.9 (1) and 64.6 (1)°. In the crystal, mol-ecules are linked by C-H⋯π inter-actions, forming a three-dimensional supra-molecular network.

Crystal structure of (Z)-3-(4-meth-oxy-benzyl-idene)-2,3-di-hydro-benzo[b][1,4]thia-zepin-4(5H)-one.

In the title compound, C17H15NO2S, the two C atoms linking the S and carbonyl C atoms of the seven-membered thia-zepine ring are disordered over two sites, with occupancies of 0.511 (4) and 0.489 (4); both disorder components adopt distorted twist-boat conformations. In the crystal, N-H⋯O and C-H⋯O hydrogen bonds link inverted-related mol-ecules into dimers, incorporating R 1 (2)(6) and R 2 (2)(8) ring motifs; the acceptor carbonyl O atom is bifurcated. These dimers are further linked by C-H⋯O hydrogen bonds, forming supra-molecular tapes running along the a axis.

Crystal structure of methyl 6-meth-oxy-11-(4-meth-oxy-phen-yl)-16-methyl-14-phenyl-8,12-dioxa-14,15-di-aza-tetra-cyclo-[8.7.0.0(2,7).0(13,17)]hepta-deca-2(7),3,5,13(17),15-penta-ene-10-carboxyl-ate.

In the title compound, C30H28N2O6, the pyran ring adopts a slightly distorted half-chair conformation and the pyrone ring adopts an envelope conformation, with the C atom bearing the carboxyl-ate group as the flap. The pyrazole ring [maximum deviation = 0.002 (2) Å] forms a dihedral angle of 13.2 (1)° with the attached benzene ring. The near-planar atoms of the pyran ring and the pyrazole ring are close to coplanar, the dihedral angles between their mean planes being 6.4 (1)°. The dihedral angle between the pyrone ring and the benzene ring of the chromene unit is 10.7 (1)°. The mol-ecular conformation is stabilized by an intra-molecular C-H⋯O hydrogen bond, which generates an S(6) ring motif. In the crystal, C-H⋯O inter-actions generate supra-molecular chains propagating in [100] and these are connected into double layers that stack along the c-axis direction by weak π-π inter-actions between pyrazole rings [centroid-centroid distance = 3.801 (1) Å].

Crystal structure of methyl 2-[2,4-bis-(4-fluoro-phen-yl)-3-aza-bicyclo-[3.3.1]nonan-9-yl-idene]hydrazine-carboxyl-ate.

In the title compound, C22H23F2N3O2, the bicyclic ring system exists in a twin-chair conformation with an equatorial disposition of the 4-fluoro-phenyl groups on the heterocycle. These aromatic rings are inclined to one another by 19.4 (1)°. In the crystal, mol-ecules are linked by pairs of N-H⋯O and C-H⋯O hydrogen bonds into inversion dimers, incorporating R 1 (2)(7) and R 2 (2)(8) ring motifs; the same O atom accepts both hydrogen bonds. These dimers are further linked by a pair of C-H⋯F hydrogen bonds, enclosing R 2 (2)(28) ring motifs, forming supra-molecular chains along [010]. The NH group of the pyridine ring is not involved in hydrogen bonding, probably due to the steric hindrance of the fluoro-phenyl groups.

Glyceraldehyde-3-phosphate dehydrogenase of the parasitic nematode Haemonchus contortus binds to complement C3 and inhibits its activity.

Haemonchus contortus is an economically important gastrointestinal parasite that infects primarily sheep and goats. To survive inside the host, the parasite must overcome the host immune response. In this study, we have identified and characterized a complement-C3-binding protein (H.c-C3BP) from this parasite employing biochemical and molecular biology tools. Initially, a truncated form of the protein was isolated from the excretory-secretory products of the parasite using C3-Sepharose column that facilitated its identification by mass spectroscopy. Subsequently, the parent molecule was generated in E. coli, and sequence analysis confirmed it as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH reacted with the antiserum raised against the truncated protein, and the truncated protein reacted with anti-GAPDH antiserum. The protein inhibited complement function as measured by haemolytic assay and membrane attack complex (MAC) formation. Sera from H. contortus-infected animals reacted with GAPDH as well as the truncated form of the protein, which further lend support to protein secretion. Thus, the C3-binding property of H. contortus GAPDH is a new function, and it represents a new entity of complement-binding protein. Identification and characterization of H.c-C3BP should facilitate development of new therapeutics considering a key role of this protein in immune modulation.

3-(4-Methoxybenzyl)-1,5-benzo-thiazepin-4(5H)-one.

In the title compound, C17H15NO2S, the thia-zepine ring adopts a slightly distorted twist-boat conformation. The dihedral angle between the mean plane of the benzo-thia-zepin ring system and the benzene ring is 65.7 (1)°. In the crystal, pairs of N-H⋯O hydrogen bonds link inversion-related mol-ecules into dimers, generating R2 (2) (8) ring motifs. These dimers are further linked by C-H⋯π and π-π inter-actions [inter-centroid distance between the benzene rings of the benzo-thia-zepine unit = 3.656 (3) Å] into a three-dimensional supra-molecular network.

(Z)-3-(3,4-Di-meth-oxy-benz-yl)-1,5-benzo-thia-zepin-4(5H)-one.

In the title compound, C18H17NO3S, the thia-zepine ring adopts a slightly distorted twist-boat conformation. The dihedral angle between the mean plane of the benzo-thia-zepin ring system and the benzene ring is 60.3 (1)°. In the crystal, mol-ecules are linked by two pairs of inversion-related N-H⋯O and C-H⋯O hydrogen bonds, generating alternating R 2 (2)(8) and R 2 (2)(6) ring motifs, respectively, in a zigzag supra-molecular chain that runs along the c axis. These chains stack along the a axis via S⋯C [3.424 (2) Å] contacts. A three-dimensional supra-molecular network is consolidated by C-H⋯π and π-π inter-actions [inter-centroid distance between di-meth-oxy-benzene rings = 3.815 (1) Å]. The crystal studied was a non-merohedral twin, with a refined value of the minor twin fraction of 0.2477 (6) .

(6'R*,7'R*)-7'-(1,3,-Diphenyl-1H-pyrazol-4-yl)-1,2,5',6',7',7a',3'',4''-octa-hydro-1'H,2''H-dispiro-[acenaphthyl-ene-1,5'-pyrrolo-[1,2-c][1,3]thia-zole-6',3''-[1]benzopyran]-2,4''-dione.

In the title compound, C40H29N3O3S, the pyran ring adopts a sofa conformation, the thia-zolidine ring adopts a twisted conformation and the pyrrolidine ring adopts an envelope conformation with the N atom as the flap. The pyrazole ring is essentially planar [maximum deviation = 0.002 (2) Å] and forms dihedral angles of 4.8 (1) and 39.0 (1)°, respectively, with the benzene rings attached to the N and C atoms. The acenapthylene ring system is approximately planar [maximum deviation = 0.058 (2) Å] and forms dihedral angles of 85.9 (1) and 48.5 (1)°, respectively, with the pyrollothia-zole and chromene ring systems. The mol-ecular conformation is stabilized by three weak intra-molecular C-H⋯O hydrogen bonds, which generate one S(8) and two S(6) ring motifs. In the crystal, pairs of C-H⋯O hydrogen bonds link centrosymmetrically related mol-ecules into dimers, generating R 2 (2)(14) ring motifs. The crystal packing also features pairs of C-H⋯π inter-actions, which link the dimers into a supra-molecular chain along the b axis.

(Z)-3-(3,4-Dimeth-oxy-benzyl-idene)-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one.

In the title compound, C18H17NO3S, the seven-membered thia-zepine ring adopts a slightly distorted sofa conformation. The dihedral angle between the mean plane of the benzothia-zepine ring system and the benzene ring is 5.9 (1)°. The mol-ecular conformation is stabilized by an intra-molecular C-H⋯S hydrogen bond, which generates an S(7) ring motif. In the crystal, N-H⋯O and C-H⋯O hydrogen bonds link inversion-related mol-ecules into dimers, incorporating R 1 (2)(6) and R 2 (2)(8) ring motifs; the acceptor O atom is bifurcated. These dimers are further linked by C-H⋯O hydrogen bonds, forming supra-molecular tapes running along the a axis. These are connected into the three-dimensional architecture by C-H⋯π inter-actions.

(Z)-3-(2,4-Dichloro-benz-yl)-1,5-benzo-thia-zepin-4(5H)-one.

In the title compound, C16H11Cl2NOS, the seven-membered thia-zepine ring adopts a distorted twist-boat conformation. The dihedral angle between the mean plane of the benzothia-zepine ring system and the benzene ring is 78.6 (1)°. The mol-ecular conformation is stabilized by a weak intra-molecular C-H⋯Cl hydrogen bond, which generates an S(5) ring motif. In the crystal, pairs of N-H⋯O hydrogen bonds link inversion-related mol-ecules into dimers, generating R 2 (2)(8) ring motifs. The crystal packing also features alternating π-π inter-actions between benzothia-zepine benzene rings [inter-centroid distance = 3.740 (3) Å] and dichloro-benzene rings [inter-centroid distance = 3.882 (3) Å] to consolidate a three-dimensional architecture.

catena-Poly[[bis-(thio-cyanato-κN)cobalt(II)]-di-µ-thio-urea-κ(4)S:S].

In the title polymeric complex, [Co(NCS)(2){SC(NH(2))(2)}(2)](n), the asymmetric unit comprises a Co(II) ion, which is situated on an inversion centre, an N-bound thio-cyanate anion and a µ(2)-bridging thio-urea mol-ecule. The Co(II) atom is coordinated in a distorted octa-hedral fashion within an N(2)S(4) donor set. The bridging thio-urea ligands link Co(II) ions into a polymeric chain extending along [100]. The mol-ecular conformation is stabilized by intra-molecular N-H⋯N hydrogen bonds, which generate S(6) ring motifs. The crystal packing is stabilized by N-H⋯S inter-actions, which connect the chains into a three-dimensional architecture.

2-(2-Nitro-phen-yl)-1,3-benzothia-zole.

In the title compound, C(13)H(8)N(2)O(2)S, the essentially planar benzothia-zole system [maximum deviation = -0.012 (1) Šfor the S atom] is oriented at a dihedral angle of 48.3 (1)° with respect to the benzene ring. The nitro group is substanti-ally twisted from the plane of its attached benzene ring [dihedral angle = 52.0 (1)°]. The crystal packing features C-H⋯O hydrogen bonds, which generate C(6) helical chains propagating along [010]. Weak C-H⋯π inter-actions also occur in the crystal.

2-[Hy-droxy(2-meth-oxy-phenyl)methyl]acrylonitrile.

In the title compound, C(11)H(11)NO(2), the mean planes formed by the benzene ring and the C and N atoms of the acryl group are almost orthogonal to each other, with a dihedral angle of 85.7 (1)°. During the structure analysis, it was observed that the unit cell contains large accessible voids, with a volume of 186.9 Å(3), which may host disordered solvent mol-ecules. This affects the diffraction pattern, mostly at low scattering angles. Density identified in these solvent-accessible areas was calculated and corrected for using the SQUEEZE routine in PLATON [Spek (2009 ▶), Acta Cryst. D65, 148-155]. Despite the presence of the hy-droxy group in the mol-ecule, no classical or nonclassical hydrogen bonds are observed in the structure. This may reflect the fact that the O-H group points towards the solvent-accessible void.

Aqua-(2,2'-bipyridine-κ²N,N')(2-methyl-malonato-κ²O¹,O³)copper(II) dihydrate.

In the title compound, [Cu(C4H4O4)(C10H8N2)(H2O)]·2H2O, the Cu(II) ion displays a slightly distorted square-pyramidal coordination. The water mol-ecule at the apical position shows a long bond [Cu-O = 2.276 (2) Å]. The basal plane is formed by two N atoms of the 2,2'-bipyridine ligand and two carboxyl-ate O atoms from a malonate group. The five-membered chelate ring is almost planar [maximum deviation = -0.006 (2) Å], while the six-membered chelate ring defined by the malonate ligand adopts a distorted boat conformation. In the crystal, Cu(II) complex mol-ecules and lattice water mol-ecules are connected by O-H⋯O and C-H⋯O hydrogen bonds. The crystal packing is further stabilized by π-π inter-actions [centroid-centroid distances = 3.563 (2)-3.828 (2) Å].