Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines.

Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure-activity relationship. The FKB derivatives 16 (IC50 = 6.50 ± 0.40 and 4.12 ± 0.20 µg/mL), 15 (IC50 = 5.50 ± 0.35 and 6.50 ± 1.40 µg/mL) and 13 (IC50 = 7.12 ± 0.80 and 4.04 ± 0.30 µg/mL) exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC50 = 8.90 ± 0.60 and 6.80 ± 0.35 µg/mL) and 22 (IC50 = 8.80 ± 0.35 and 14.16 ± 1.10 µg/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC50 = 7.70 ± 0.30 and 5.90 ± 0.30 µg/mL) against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F) in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by ¹H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques.

Design, synthesis and cytotoxic effects of curcuminoids on HeLa, K562, MCF-7 and MDA-MB-231 cancer cell lines.

BACKGROUND: Curcumin is one of the leading compound extracted from the dry powder of Curcuma longa (Zingiberaceae family), which possess several pharmacological properties. However, in vivo administration exhibited limited applications in cancer therapies. RESULTS: Twenty-four curcumin derivatives have synthesized, which comprises cyclohexanone 1-10, acetone 11-17 and cyclopentanone 18-24 series. All the curcuminoids were synthesized by the acid or base catalyzed Claisen Schmidt condenstion reactions, in which ß-diketone moiety of curcumin was modified with mono-ketone. These curcuminoids 1-24 were screened against HeLa, K562, MCF-7 (an estrogen-dependent) and MDA-MB-231 (an estrogen-independent) cancer cell lines. Among them, acetone series 11-17 were found to be more selective and potential cytotoxic agents. The compound 14 was exhibited (IC50 = 3.02 ± 1.20 and 1.52 ± 0.60 µg/mL) against MCF-7 and MDA-MB-231 breast cancer cell lines. Among the cyclohexanone series, the compound 4 exhibited (IC50 = 11.04 ± 2.80, 6.50 ± 01.80, 8.70 ± 3.10 and 2.30 ± 1.60 µg/mL) potential cytotoxicity against four proposed cancer cell lines, respectively. All the curcucminoids were characterized with the detailed 1H NMR, IR, UV-Vis, and mass spectroscopic techniques. The structure of compound 4 was confirmed by using the single X-ray crystallography. Additionally, we are going to report the first time spectral data of (2E,6E)-2,6-bis(2-methoxybenzylidene)cyclohexanone (1). Structure-activity relationships revealed that the mono-carbonyl with 2,5-dimethoxy substituted curcuminoids could be an essential for the future drugs against cancer diseases. CONCLUSIONS: Curcuminoids with diferuloyl(4-hydroxy-3-methoxycinnamoyl) moiety with mono carbonyl exhibiting potential cytotoxic properties. The compound 14 was exhibited (IC50 = 3.02 ± 1.20 and 1.52 ± 0.60 µg/mL) against MCF-7 and MDA-MB-231 breast cancer cell lines.

The crystal structure of zwitterionic 2-{[(4-imin-iumyl-3-methyl-1,4-di-hydro-pyridin-1-yl)meth-yl]carbamo-yl}benzoate hemihydrate.

The asymmetric unit of the title compound, C15H15N3O3·0.5H2O, comprises two 2-{[(4-iminiumyl-3-methyl-1,4-di-hydro-pyridin-1-yl)meth-yl]carbamo-yl}benzoate zwitterions (A and B) and a water mol-ecule. The dihedral angles between the pyridine and phenyl rings in the zwitterions are 53.69 (10) and 73.56 (11)° in A and B, respectively. In the crystal, mol-ecules are linked by N-H⋯O, O-H⋯O, C-H⋯O and C-H⋯π(ring) hydrogen bonds into a three-dimensional network. The crystal structure also features π-π inter-actions involving the centroids of the pyridine and phenyl rings [centroid-centroid distances = 3.5618 (12) Šin A and 3.8182 (14) Šin B].

Synthesis and Crystallographic Insight into the Structural Aspects of Some Novel Adamantane-Based Ester Derivatives.

Adamantyl-based compounds are commercially important in the treatments for neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their values in drug design are chronicled as multi-dimensional. In the present study, a series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a-q), and 2-(adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone with various carboxylic acids using potassium carbonate in dimethylformamide medium at room temperature. Three-dimensional structures studied using X-ray diffraction suggest that the adamantyl moiety can serve as an efficient building block to synthesize 2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore, three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation of albumin denaturation.

Crystal structure of tetra-aqua-bis(3,5-di-amino-4H-1,2,4-triazol-1-ium)cobalt(II) bis-[bis-(pyridine-2,6-di-carboxyl-ato)cobaltate(II)] dihydrate.

The asymmetric unit of the title compound, [Co(C2H6N5)2(H2O)4][Co(C7H3NO4)2]2·2H2O, features 1.5 Co(II) ions (one anionic complex and one half cationic complex) and one water mol-ecule. In the cationic complex, the Co(II) atom is located on an inversion centre and is coordinated by two triazolium cations and four water mol-ecules, adopting an octa-hedral geometry where the N atoms of the two triazolium cations occupy the axial positions and the O atoms of the four water mol-ecules the equatorial positions. The two triazole ligands are parallel offset (with a distance of 1.38 Šbetween their planes). In the anionic complex, the Co(II) ion is six-coordinated by two N and four O atoms of the two pyridine-2,6-di-carboxyl-ate anions, exhibiting a slightly distorted octa-hedral coordination geometry in which the mean plane of the two pyridine-2,6-di-carboxyl-ate anions are almost perpendicular to each other, making a dihedral angle of 85.87 (2)°. In the crystal, mol-ecules are linked into a three-dimensional network via C-H⋯O, C-H⋯N, O-H⋯O and N-H⋯O hydrogen bonds.

Synthesis, structural and antioxidant studies of some novel N-ethyl phthalimide esters.

A series of N-ethyl phthalimide esters 4(a-n) were synthesized and characterized by spectroscopic studies. Further, the molecular structure of majority of compounds were analysed by single crystal X-ray diffraction studies. The X-ray analysis revealed the importance of substituents on the crystal stability and molecular packing. All the synthesized compounds were tested for in vitro antioxidant activity by DPPH radical scavenging, FRAP and CUPRAC methods. Few of them have shown good antioxidant activity.

Investigation of supramolecular synthons and structural characterisation of aminopyridine-carboxylic acid derivatives.

BACKGROUND: Co-crystal is a structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts. The main advantage of co-crystals is their ability to generate a variety of solid forms of a drug that have distinct physicochemical properties from the solid co-crystal components. In the present investigation, five co-crystals containing 2-amino-6-chloropyridine (AMPY) moiety were synthesized and characterized. RESULTS: The crystal structure of 2-amino-6-chloropyridine (AMPY) (I), and the robustness of pyridine-acid supramolecular synthon were discussed in four stoichiometry co-crystals of AMPY…BA (II), AMPY…2ABA (III), AMPY…3CLBA (IV) and AMPY…4NBA (V). The abbreviated designations used are benzoic acid (BA), 2-aminobenzoic acid (2ABA), 3-chlorobenzoic acid (3CLBA) and 4-nitrobenzoic acid (4NBA). All the crystalline materials have been characterized by (1)HNMR, (13)CNMR, IR, photoluminescence, TEM analysis and X-ray diffraction. The supramolecular assembly of each co-crystal is analyzed and discussed. CONCLUSIONS: Extensive N---H · · · N/N---H · · · O/O---H · · · N hydrogen bonds are found in (I-V), featuring different supramolecular synthons. In the crystal structure, for compound (I), the 2-amino-6-chloropyridine molecules are linked together into centrosymmetric dimers by hydrogen bonds to form homosynthon, whereas for compounds (II-V), the carboxylic group of the respective acids (benzoic acid, 2-aminobenzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid) interacts with pyridine molecule in a linear fashion through a pair of N---H · · · O and O---H · · · N hydrogen bonds, generating cyclic hydrogen-bonded motifs with the graph-set notation [Formula: see text] , to form heterosynthon. In compound (II), another intermolecular N---H · · · O hydrogen bonds further link these heterosynthons into zig-zag chains. Whereas in compounds (IV) and (V), these heterosynthons are centrosymmetrically paired via N---H · · · O hydrogen bonds and each forms a complementary DADA [D = donor and A = acceptor] array of quadruple hydrogen bonds, with graph-set notation [Formula: see text], [Formula: see text] and [Formula: see text].

Heteroaryl chalcones: design, synthesis, X-ray crystal structures and biological evaluation.

Chalcone derivatives have attracted increasing attention due to their numerous pharmacological activities. Changes in their structures have displayed high degree of diversity that has proven to result in a broad spectrum of biological activities. The present study highlights the synthesis of some halogen substituted chalcones 3(a-i) containing the 5-chlorothiophene moiety, their X-ray crystal structures and the evaluation of possible biological activities such as antibacterial, antifungal and reducing power abilities. The results indicate the tested compounds show a varied range of inhibition values against all the tested microbial strains. Compound 3c with a p-fluoro substituent on the phenyl ring exhibits elevated antimicrobial activity, whereas the compounds 3e and 3f displayed the least antimicrobial activities. The compounds 3d, 3e, 3f and 3i showed good ferric and cupric reducing abilities, and the compounds 3b and 3c showed the weakest reducing power in the series.

Structural correlation of some heterocyclic chalcone analogues and evaluation of their antioxidant potential.

A series of six novel heterocyclic chalcone analogues 4(a-f) has been synthesized by condensing 2-acetyl-5-chlorothiophene with benzaldehyde derivatives in methanol at room temperature using a catalytic amount of sodium hydroxide. The newly synthesized compounds are characterized by IR, mass spectra, elemental analysis and melting point. Subsequently; the structures of these compounds were determined using single crystal X-ray diffraction. All the synthesized compounds were screened for their antioxidant potential by employing various in vitro models such as DPPH free radical scavenging assay, ABTS radical scavenging assay, ferric reducing antioxidant power and cupric ion reducing antioxidant capacity. Results reflect the structural impact on the antioxidant ability of the compounds. The IC0 values illustrate the mild to good antioxidant activities of the reported compounds. Among them, 4f with a p-methoxy substituent was found to be more potent as antioxidant agent.

1-[5-(2H-1,3-Benzodioxol-5-yl)-3-(4-methyl-phen-yl)-2-pyrazolin-1-yl]ethanone.

In the title compound, C19H18N2O3, the pyrazoline ring is close to being planar (r.m.s. deviation = 0.035 Å) and subtends dihedral angles of 2.11 (8) and 82.63 (8)° with the p-tolyl and benzene rings, respectively. In the crystal, C-H⋯O and C-H⋯N hydrogen bonds link the mol-ecules, forming a three-dimensional network. A weak C-H⋯π inter-action involving the benzene ring is also observed.

3-(4-Methyl-phen-yl)-4-[(thio-semi-carba-zono)meth-yl]-1,2,3-oxa-diazol-3-ium-5-olate 1,4-dioxane hemisolvate.

The asymmetric unit of the title compound, C11H11N5O2S·0.5C4H8O2, contains one 3-(p-tol-yl)sydnone 4-thio-semi-carba-zone mol-ecule and a half mol-ecule of 1,4-dioxane, which lies abount an inversion centre. The sydnone ring is almost planar, with a maximum deviation of 0.002 (1) Å, and forms a dihedral angle of 46.31 (5)° with the benzene ring. In the crystal, the two components are linked into a tape along [01-1] by N-H⋯O and N-H⋯S hydrogen bonds. The crystal structure is further stabilized by C-H⋯O and C-H⋯π inter-actions, forming a three-dimensional network.

Bis-(3,5-diamino-4H-1,2,4-triazol-1-ium) 3,4-dioxocyclo-butane-1,2-diolate.

The asymmetric unit of the title compound, 2C2H6N5(+)·C4O4(2-), contains two 3,5-diamino-4H-1,2,4-triazolium cations and one squarate dianion. The squaric acid mol-ecule donated one H atom to each of the two 3,5-diamino-1,2,4-triazole mol-ecules at their N atoms. The squaric acid dianion has four C-O bonds which are shorter than a normal single C-O bond (1.426 Å) and are slightly longer than a normal C=O bond (1.23 Å), which indicates the degree of electron delocalization in the dianion. In the crystal, the cations and dianions are linked by N-H⋯N and N-H⋯O hydrogen bonds into a three-dimensional network.

Synthesis and crystal structures of N-substituted pyrazolines.

Four pyrazole compounds, 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde (1), 5-(4-bromophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehyde (2), 1-[5-(4-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]ethanone (3) and 1-[3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]propan-1-one (4), have been prepared by condensing chalcones with hydrazine hydrate in the presence of aliphatic acids, namely formic acid, acetic acid and propionic acid. The structures were characterized by X-ray single crystal structure determination. The dihedral angles formed between the pyrazole and the fluoro-substituted rings are 4.64(7)° in 1, 5.3(4)° in 2 and 4.89(6)° in 3. In 4, the corresponding angles for molecules A and molecules B are 10.53(10)° and 9.78(10)°, respectively.

2-(4-Meth-oxy-phenyl)-2-oxoethan-aminium chloride.

In the cation of the title compound, C(9)H(12)NO(2) (+)·Cl(-), the dihedral angle between the 2-oxoethanaminium N-C-C(=O)- plane [maximum deviation = 0.0148 (12) Å] and the benzene ring is 7.98 (8)°. The meth-oxy group is approximately in-plane with the benzene ring, with a C-O-C-C torsion angle of -2.91 (18)°. In the crystal, the cations and chloride anions are connected by N-H⋯Cl and C-H⋯Cl hydrogen bonds, forming a layer parallel to the bc plane. A C-H⋯π inter-action further links the layers.

1-[5-(4-Bromo-phen-yl)-3-(4-fluoro-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]butan-1-one.

In the title compound, C(19)H(18)BrFN(2)O, the benzene rings form dihedral angles of 5.38 (7) and 85.48 (7)° with the mean plane of the 4,5-dihydro-1H-pyrazole ring (r.m.s. deviation = 0.0849 Å), which approximates to an envelope conformation with the -CH(2)- group as the flap. The dihedral angle between the benzene rings is 82.86 (7)°. In the crystal, C-H⋯F and C-H⋯O hydrogen bonds link the mol-ecules to form inversion dimers and together these generate chains along [011]. The crystal packing also features C-H⋯π inter-actions.

2-Cyclo-pentyl-idenehydrazine-carboxamide.

The asymmetric unit of the title compound, C(6)H(11)N(3)O, consists of two independent mol-ecules in which the cyclo-pentane rings adopt envelope conformations with CH(2) grouping as the flap and the semicarbazone groups are essentially planar, with maximums deviation of 0.0311 (12) and 0.0285 (12) Å. In the crystal, N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds link the mol-ecules to form sheets lying parallel to the ab plane.

1-[2,6-Dichloro-4-(trifluoro-meth-yl)phen-yl]-3,4-dimethyl-pyrano[2,3-c]pyrazol-6(1H)-one.

In the title compound, C(15)H(9)Cl(2)F(3)N(2)O(2), the 1,6-dihydro-pyrano[2,3-c]pyrazole ring system is almost planar, with a maximum deviation of 0.0226 (14) Å, and forms a dihedral angle of 69.90 (6)° with the benzene ring. In the crystal, mol-ecules are linked into a helical chain along the c axis by C-H⋯O hydrogen bonds.

N-(4-Chloro-phen-yl)-2,2-diphenyl-acetamide.

In the title compound, C(20)H(16)ClNO, an S(6) ring motif is formed via an intra-molecular C-H⋯O hydrogen bond. The chloro-substituted benzene ring is almost perpendicular to the benzene rings, forming dihedral angles of 87.33 (9) and 88.69 (9)°. The dihedral angle between the benzene rings is 87.17 (9)°. In the crystal, mol-ecules are linked into chains parallel to the c axis by inter-molecular N-H⋯O hydrogen bonds. The crystal packing also features weak C-H⋯π inter-actions involving the chloro-substituted ring.

1-[5-(4-Bromo-phen-yl)-3-(4-fluoro-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]ethanone.

In the title mol-ecule, C(17)H(14)BrFN(2)O, the benzene rings form dihedral angles of 6.58 (6) and 85.31 (6)° with the mean plane of the 4,5-dihydro-1H-pyrazole ring (r.m.s. deviation = 0.0231 Å). The latter ring is planar with a maximum deviation of 0.032 (1) ŠThe dihedral angle between the benzene rings is 78.75 (6)°. In the crystal, weak C-H⋯O and C-H⋯F hydrogen bonds link the mol-ecules into corrugated layers parallel to the ab plane.

(2E)-1-(4,4''-Difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4'-yl)-3-(2-fluoro-phen-yl)prop-2-en-1-one.

In the title compound, C(28)H(19)F(3)O(2), the central benzene ring forms dihedral angles of 48.69 (6), 60.93 (6) and 42.06 (6)° with the fluoro-benzene rings. In the crystal, inter-molecular C-H⋯O and C-H⋯F hydrogen bonds link the mol-ecules, forming an undulating two-dimensional network parallel to the bc plane. C-H⋯π inter-actions further consolidate the crystal packing.