Synthesis of dimeric 1,2-benzothiazine 1,1-dioxide scaffolds: molecular structures, Hirshfeld surface analysis, DFT and enzyme inhibition studies.

1,2-Benzothiazines are bioactive compounds with diverse pharmacological properties. We report here the synthesis of a series of dimers containing 1,2-benzothiazine scaffolds as potential pharmacophores. The characterization of compounds was done using analytical techniques such as FT-IR, 1H NMR, and elemental analyses. The molecular structures of the compounds (5-8) were confirmed by X-ray crystallography. The molecular interactions in compounds (5-8) were determined by Hirshfeld Surface Analysis (HSA). Density functional theory (DFT) investigations were carried out to calculate vibrational properties, NMR behaviour, dipole moments, molecular electrostatic potential (MEP), frontier molecular orbital (FMO), natural bonding orbital (NBO) analysis and global reactivity descriptors. The global reactivity descriptors indicated the charge transfer reactions and stabilized as follows: 8 > 7 > 6 > 5. In FMO analysis a substantial HOMO-LUMO gap, ranging from 4.43 to 5.12 eV, with high LUMO values was observed for all compounds, while the highest value for linear polarizability was found in compound 8. The in vitro and in silico studies confirm that compound 8 is more active toward AChE and BChE enzymes.

Hybrid compounds from chalcone and 1,2-benzothiazine pharmacophores as selective inhibitors of alkaline phosphatase isozymes.

Chalcones and 1,2-benzothiazines are two important classes of bioactive compounds, each scaffold endowed with diverse pharmacological activities. Combining both of these pharmacophores in a single molecule was aimed to yield multi-modal agents. Herein, we report a series of hybrid compounds 3a-3o derived from chalcones and 1,2-benzothiazine cores. They were synthesized from commercially available sodium saccharin, and the resulting 1,2-benzothiazine-derived ketone was then condensed with aromatic aldehydes in an aldol condensation to obtain the respective chalcones. The compounds were characterized using different analytical techniques including FT-IR, NMR spectroscopy, mass spectrometry and X-ray crystallography. Some synthesized chalcones revealed potent and/or selective inhibitory properties towards alkaline phosphatase isozymes transiently expressed in COS-7 cells. A detailed structure-activity and selectivity study was carried out with regard to the effect of different substituents at ortho-, meta- and para-positions of the phenyl residue. Compound 3c was the most effective human intestinal alkaline phosphatase (h-IAP) inhibitor (IC50 value of 1.04 µM), while it was not active against human tissue non-specific alkaline phosphatase (h-TNAP) isozyme. In contrast, 3i was a selective inhibitor of h-TNAP with IC50 values of 0.25 ±â€¯0.01 µM. The possible binding interactions of the most effective inhibitors of h-TNAP and h-IAP were obtained from molecular docking studies.

Potential of Nigella sativa seed aqueous extract in ameliorating quinine-induced thrombocytopenia in rats.

Dengue infection is rapidly spreading in most of the countries of south Asia. It is of utmost importance to explore the plants with "anti-thrombocytopenic activity" the dreadful response of dengue fever. The present study was conducted to investigate the potential of aqueous extract of Nigella sativa (black cumin) seeds in alleviating the severity of dengue disease by raising the platelet count (PLT). Serum samples of thirty patients with dengue hemorrhagic fever (DHF) were analysed for different biochemical parameters. When compared with control groups, the patients were found with very low PLT count (7.62 fold), reduced antioxidant levels; catalase (1.4 fold), ascorbic acid (1.1 fold), bilirubin (1.06 fold), and severe deficiency of micronutrient concentrations; cobalt (2.27 fold), iron (2.35 fold) and nickel (71.46 fold). Similar parameters were studied in albino rats to observe the changes in serum levels of biochemical markers, after administration of single dose of choloroquine phosphate (IM, 1.5 mL saline). The drug successfully induced thrombocytopenia along with significant decrease in levels of antioxidants and trace metals. Administration of N. sativa aqueous seed extract (15.25 mg/kg/bw) for 12 days resulted in an increase in PLT count (1.59 fold) as compared to control group. N. sativa post-treatment was found effective in elevating the serum levels of catalase, ascorbic acid, and bilirubin (1.06, 1.58 and 0.4 folds respectively). However, the N. sativa pre-treatment was useful in increasing the levels of micronutrients; iron, nickel and cobalt when compared to quinine-induced group. From the above findings it was suggested that N. sativa seed aqueous extract supplementation would be a promising solution for declined PLT count and associated consequences.

Anti-Inflammatory Oxicams as Multi-donor Ligand Systems: pH- and Solvent-Dependent Coordination Modes of Meloxicam and Piroxicam to Ru and Os.

The nitrogen- and sulfur-containing 1,2-benzothiazines meloxicam and piroxicam are widely used as nonsteroidal anti-inflammatory drugs. Intrigued by the presence of multiple donor atoms and therefore potentially rich coordination chemistry, we prepared a series of organometallic Ru and Os compounds with meloxicam and piroxicam featuring either as mono- or bidentate ligand systems. The choice of the solvent and the pH value was identified as the critical parameter to achieve selectively mono- or bidentate coordination. The coordination modes were confirmed experimentally by NMR spectroscopy and single crystal X-ray diffraction analysis. Using DFT calculations, it was established that complexes in which meloxicam acts as a bidentate N,O donor are energetically more favorable than coordination as O,O and S,O donor systems. Since meloxicam and piroxicam derivatives have shown anticancer activity in the past, we aimed to compare the complexes with mono- and bidentate ligands on their in vitro anticancer activity. However, stability studies revealed that only the latter complexes were stable in [D6 ]DMSO/D2 O (5:95) and therefore no direct comparisons could be made. The meloxicam complexes 1 and 2 showed moderate cytotoxicity, whereas the piroxicam derivatives 5 and 6 were hardly active against the utilized cell lines.

Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.

Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 µM. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 µM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9±1.16 to -35.1±0.13 in case of Cathepsin D, while from -24.0±0.10 to -29.5±0.10 in case of Plasmepsin-II.

2-(1H-Benzimidazol-2-yl)-N-[(E)-(dimethyl-amino)-methyl-idene]benzene-sulfonamide.

The asymmetric unit of the title compound, C(16)H(16)N(4)O(2)S, contains two mol-ecules (A and B) with similar conformations: the benzene rings are oriented at dihedral angles of 80.94 (10)° and 84.54 (10)° with their adjacent 1H-benzimidazole groups. In the crystal, the mol-ecules are connected by N-H⋯N hydrogen bonds, forming separate C(4) chains of both the A and B mol-ecules along [010]. The A and B chains are cross-linked by several C-H⋯O inter-actions involving the benzene rings and the sulfonyl groups, which lead to R(2) (1)(5) loops in the linkage of the chains.

4-Hy-droxy-2-methyl-1,1-dioxo-N-phenyl-2H-1λ(6),2-benzothia-zine-3-carboxamide.

In the title mol-ecule, C(16)H(14)N(2)O(4)S, the thia-zine ring adopts a twist chair conformation with the N and adjacent C atom displaced by 0.966 (3) and 0.386 (4) Å, respectively, on the same side of the mean plane formed by the remaining ring atoms. The dihedral angle between the mean planes of the benzene rings is 37.65 (10)°. The mol-ecular structure features an intra-molecular O-H⋯O hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds.

2-[2-(2-Bromo-phen-yl)-2-oxoeth-yl]-1λ(6),2-benzothia-zole-1,1,3-trione.

The asymmetric unit of the title compound, C(15)H(10)BrNO(4)S, contains two different conformers in which the benzisothia-zole rings are essentially planar, with r.m.s. deviations of 0.012 and 0.017 Å. The mean planes of the benzene rings form dihedral angles 70.49 (13) and 72.79 (11)° with the benzisothia-zole rings. The orientation of the Br atoms in the two conformers exhibit the most pronounced difference, with opposing orientations in the two mol-ecules. The crystal structure is stabilized by π-π inter-actions between the benzene rings of the benzisothia-zole moieties of one mol-ecule and bromo-benzene rings of the other mol-ecule, with distances between the ring centroids of 3.599 (3) and 3.620 (3) Å, respectively. The crystal packing is further consolidated by pairs of weak inter-molecular C-H⋯O hydrogen bonds, which form inversion dimers.

2,6-Dibromo-4-chloro-aniline.

The title compound, C(6)H(4)Br(2)ClN, is almost planar (r.m.s. deviation = 0.024 Å) and two intra-molecular N-H⋯Br hydrogen bonds generate S(5) rings. In the crystal, N-H⋯Br hydrogen bonds link the mol-ecules into chains propagating in [010].

N-Benzyl-4-hy-droxy-2-methyl-1,1-dioxo-2H-1λ(6),2-benzothia-zine-3-carboxamide.

In the title mol-ecule, C(17)H(16)N(2)O(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.546 (4) and 0.281 (4) Å, respectively, on opposite sides of the mean plane formed by the remaining ring atoms. The mol-ecular structure is stabilized by an intra-molecular O-H⋯O hydrogen bond. The two aromatic rings are inclined to one another by 42.32 (11)°. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers. The dimers are linked via a series of C-H⋯O inter-actions, leading to the formation of a three-dimensional network.

3-[Hy-droxy(3-meth-oxy-phen-yl)methyl-idene]-2-(2-oxo-2-phenyl-eth-yl)-3,4-dihydro-2H-1λ(6),2-benzothia-zine-1,1,4-trione.

In the title mol-ecule, C(24)H(19)NO(6)S, the heterocyclic thia-zine ring adopts a half-chair conformation with the S and N atoms displaced by 0.180 (5) and 0.497 (5) Å, respectively, on opposite sides of the mean plane formed by the remaining ring atoms. The benzene rings of the benzothia-zine unit and the meth-oxy-phenyl group are almost coplanar, with the dihedral angle between the mean planes of these rings being 5.9 (2)°, while the benzene ring of the 2-oxo-2-phenyl-ethyl group is inclined at 79.68 (11) and 81.01 (10)°, respectively, to these rings. The mol-ecular structure is consolidated by intra-molecular O-H⋯O and C-H⋯N inter-actions, and the crystal packing is stabilized by weak C-H⋯O hydrogen bonds.

2-[2-(3-Chloro-phen-yl)-2-oxoeth-yl]-4-hy-droxy-3-(3-meth-oxy-benzo-yl)-2H-1λ(6),2-benzothia-zine-1,1-dione.

In the title mol-ecule, C(24)H(18)ClNO(6)S, the heterocyclic thia-zine ring adopts a half chair conformation with the S and N atoms displaced by 0.318 (3) and 0.387 (3) Å, respectively, on the opposite sides from the mean plane formed by the remaining ring atoms. The benzene rings of the benzothia-zin unit and meth-oxy-benzoyl group are more or less coplanar, the dihedral angle between the mean planes of these rings being 12.37 (10)° while the chloro-phenyl ring is inclined at 81.87 (4) and 73.30 (5)°, respectively, to these rings. The mol-ecular structure is consolidated by intra-molecular O-H⋯O and C-H⋯N inter-actions and the crystal packing is stabilized by weak inter-molecular C-H⋯O hydrogen bonds.

2,3-Dihydro-1λ(6),2-benzothia-zine-1,1,4-trione.

In the title compound, C(8)H(7)NO(3)S, the benzene ring is oriented at a dihedral angle of 69.25 (7)° to the S and O atoms of the sulfonyl group. The heterocyclic ring approximates to an envelope, with the N atom in the flap position. In the crystal, mol-ecules are linked by N-H⋯O(c) (c = carbon-yl) hydrogen bonds, forming C(5) chains along [001]. Two R(2) (2)(10) loops arise from pairs of C-H⋯O hydrogen bonds and a weak aromatic π-π stacking inter-action [centroid-centorid separation = 3.8404 (11) Å] also occurs.

(2-Chloro-phen-yl)(4-hy-droxy-1,1-dioxo-2H-1,2-benzothia-zin-3-yl)methanone.

In the title mol-ecule, C(15)H(10)ClNO(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.527 (7) and 0.216 (7) Å, respectively, on opposite sides of the mean plane formed by the remaining ring atoms. The mol-ecular structure is consolidated by an intra-molecular O-H⋯O inter-action and the crystal packing is stabilized by N-H⋯O and C-H⋯O hydrogen bonds.

(2-Bromo-phen-yl)(4-hy-droxy-1,1-dioxo-2H-1,2-benzothia-zin-3-yl)methanone.

In the title mol-ecule, C(15)H(10)BrNO(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.554 (7) and 0.198 (8) Å, respectively, on opposite sides of the mean plane formed by the remaining ring atoms. The mol-ecular structure is consolidated by intra-molecular O-H⋯O inter-actions and the crystal packing features N-H⋯O and C-H⋯O hydrogen bonds.

4-Hy-droxy-2-methyl-1,1-dioxo-2H-1λ,2- benzothia-zine-3-carb-oxy-lic acid hemihydrate.

In the title compound, C(10)H(9)NO(5)S·0.5H(2)O, two geometrically different organic mol-ecules are present. The benzene rings and the carboxyl-ate groups are oriented at dihedral angles of 13.44 (4) and 21.15 (18)°. In both mol-ecules, an intra-molecular O-H⋯O hydrogen bond generates an S(6) ring. In the crystal, both moleucles form inversion dimers linked by pairs of O-H⋯O hydrogen bonds to generate R(2) (2)(8) loops. The dimers are consolidated into chains extending along [100] by bridging O-H⋯O hydrogen bonds from the water mol-ecule. A weak C-H⋯O hydrogen bond also occurs.

2,2'-(4-Methyl-4H-1,2,4-triazole-3,5-di-yl)dibenzene-sulfonamide.

In the title compound, C(15)H(15)N(5)O(4)S(2), the dihedral angles between the central 1,2,4-triazole ring and the pendant benzene rings are 55.61 (10) and 68.59 (10)°; the dihedral angle between the benzene rings is 63.66 (9)°. Intra-molecular N-H⋯N and N-H⋯O hydrogen bonds generate S(7) and S(12) rings, respectively. In the crystal, sheets extending in the (101) plane arise, with the mol-ecules linked by C-H⋯O, N-H⋯N and N-H⋯O inter-actions. A C-H⋯π inter-action further consolidates the structure.

2-(N-Cyclo-hexyl-carbamo-yl)benzene-sulfonamide.

The asymmetric unit of the title compound, C(13)H(18)N(2)O(3)S, contains two mol-ecules with similar conformations. In both mol-ecules, the cyclo-hexyl rings adopt chair conformations, with the attached N atom in an equatorial orientation and an intra-molecular N-H⋯O hydrogen bond generates an S(7) ring. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules and a C-H⋯O hydrogen bond is also observed. The crystal studied was a racemic twin.

Antimicrobial and antileishmanial studies of novel (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones.

Thirty eight heterocyclic chalcones were synthesized by condensing formylquinolines with diverse methyl arylketones. The target compounds were characterized by spectroscopic techniques (NMR, IR, MS) and elemental analysis. The X-ray crystallographic study of (2E)-3-(2-chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one (1p) was also performed for the structure confirmation. The title compounds were screened for anti-microbial and antileishmanial activities. The compounds 1c-e, 1g, 1j-m, 1p, 1r-s, 2g, 2j-p, and 2r-s were found potentially active antileishmanial agents, while 1f-i, 1l, 1o-p, 2f-i, 2l, and 2o-p showed remarkable antibacterial activity. Only compounds 1g and 2g-h exhibited significant antifungal activity.

N-(3-Chloro-phen-yl)-1,2-benzisothia-zol-3-amine 1,1-dioxide.

In the title compound, C(13)H(9)ClN(2)O(2)S, the dihedral angle between the aromatic ring systems is 6.00 (12)° and an intra-molecular C-H⋯N inter-action generates an S(6) ring. In the crystal, mol-ecules inter-act by way of C-H⋯O and N-H⋯O bonds, generating R(2) (1)(7) and R(2) (2)(10) ring motifs, and aromatic π-π stacking inter-actions [centroid-centroid separations = 3.730 (3) and 3.733 (2) Å] help to consolidate the packing.