Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents.

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC50=5.96±1.6µM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.

Ethyl 2-[2-(2,4-diphenyl-3-aza-bicyclo-[3.3.1]nonan-9-yl-idene)hydrazin-1-yl]-4-methyl-1,3-thia-zole-5-carboxyl-ate di-methyl-formamide monosolvate.

In the title mol-ecule, C27H30N4O2S·C3H7NO, the fused piperidine and cyclo-hexane rings adopt a twin chair conformation and the phenyl groups occupy equatorial sites. The phenyl rings make a dihedral angle of 40.74 (2)°. In the crystal, the di-methyl-formamide solvent mol-ecule is connected to the main mol-ecule by an N-H⋯O hydrogen bond. An additional N-H⋯O hydrogen bond connects mol-ecules into chains along [100]. Pairs of weak C-H⋯O hydrogen bonds connect inversion-related chains. The ethyl group was refined as disordered over two sets of sites with an occupancy ratio of 0.660 (17):0.340 (17).

Crystal structure of 1-(2-chloro-acet-yl)-2,6-bis-(4-fluoro-phen-yl)-3,3-di-methyl-piperidin-4-one.

In the title mol-ecule, C21H20ClF2NO2, the piperidine ring adopts a slightly distorted boat conformation. The two benzene rings form a dihedral angle of 87.43 (1)°. A weak intra-molecular C-H⋯π inter-action is observed. In the crystal, weak C-H⋯O hydrogen bonds and weak C-H⋯π inter-actions connect the mol-ecules, forming a three-dimensional network.

3-[(4-Oxo-4H-thio-chromen-3-yl)meth-yl]-4H-thio-chromen-4-one.

The title mol-ecule, C19H12S2O2, lies on a twofold rotation axis. The thio-chromonone unit is essentially planar, with a maximum deviation of 0.0491 (14) Å. The dihedral angle between the thio-chromenone ring systems is 64.48 (4)°. In the crystal, there are weak π-π stacking inter-actions, with a centroid-centroid distance of 3.7147 (9) Å.

rac-7-Methyl-3-[(7-methyl-4-oxo-chro-man-3-yl)meth-yl]-4H-chromen-4-one.

In the racemic title compound, C21H18O4, the chromone ring is essentially planar [maximum deviation from the least-squares plane = 0.026 (3) Å], with a dihedral angle of 78.18 (12)° between the benzene rings of the chromanone and chromenone moieties. In the crystal, there are weak π-π stacking inter-actions [minimum ring centroid separation = 3.9286 (17) Å].

Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERß modulation, in vitro and in vivo studies.

Eight novel ERß selective daidzein analogues (NCE1-8) were synthesized and their anti-cancer activity was evaluated by in vitro and in vivo methods. Cytotoxicity study, Receptor binding studies, Luciferase assay, cMYC & Cyclin D1 expression and Caspase 3, 8 & 9 activities were measured to ascertain the anticancer activity and mechanism. Uterotropic, anti-androgenic and anti-tumour activities were performed in rodents. The results revealed that NCEs produced anti-prostate cancer activity in DU145, LNCaP and PC3 cell lines and 50% more active than genistein. NCEs was significantly down-regulated cMYC & Cyclin D1 genes and elevated caspase 3 & 9 levels and did not show any difference in uterotropic, anti-androgenic activities. The tumour weight was also reduced. The NCE 1 and 2 have shown ERß selectivity in receptor binding studies. Daidzein with methyl substitution at R or R1 position exhibited more ERß selectivity and could be considered as lead molecules for anti-prostate cancer activity.

Efficient synthesis, spectral analysis and antimicrobial studies of nitrogen and sulfur containing spiro heterocycles from 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones.

Acetyl and propionyl group substituted thiadiazole derivatives (4a-4h, 5a-5h, 6a, 6b, 7a and 7b) have been synthesized by the cyclization of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (2a-2h, 3a and 3b) with acetic anhydride/propionic anhydride and were characterized by Elemental analysis, IR, (1)H NMR and (13)C NMR spectral analysis. Single crystal X-ray diffraction has also been recorded for compounds 4c and 5a. From the NMR and Single crystal X-ray diffraction analysis, compounds 4b-4d, 4f-4h, 5b, 5c, 5f-5h, 6a, 7a and 7b were found to adopt twin-chair conformations whereas compounds 4a, 4e, 5a, 5d, 5e and 6b adopt chair and boat conformation of cyclohexane and piperidine rings, respectively. Besides, the synthesized compounds were screened for antibacterial and antifungal activities using serial dilution method. The microbiological analysis showed that the electron withdrawing function substituted phenyl group at C-2 and C-4 of azabicyclononane based thiadiazoles 4c/4h and 5c/5h exposed significant antimicrobial activity against Salmonella typhi, Escherichia coli, Klebsiella pneumoniae, Aspergillus flavus, Aspergillus niger and Candida albicans at MIC of 6.25 µg/ml.

Different hydrogen-bonding modes in two closely related oximes.

Two closely related oximes, namely 1-chloroacetyl-3-ethyl-2,6-diphenylpiperidin-4-one oxime, C(21)H(23)ClN(2)O(2), (I), and 1-chloroacetyl-2,6-diphenyl-3-(propan-2-yl)piperidin-4-one oxime, C(22)H(25)ClN(2)O(2), (II), despite their identical sets of hydrogen-bond donors and acceptors, display basically different hydrogen-bonding patterns in their crystal structures. While the molecules of (I) are organized into typical centrosymmetric dimers, created by oxime-oxime O-H...N hydrogen bonds, in the structure of (II) there are infinite chains of molecules connected by O-H...O hydrogen bonds, in which the carbonyl O atom from the chloroacetyl group acts as the hydrogen-bond acceptor. Despite the differences in the hydrogen-bond schemes, the -OH groups are always in typical anti positions (C-N-O-H torsion angles of ca 180 degrees ). The oxime group in (I) is disordered, with the hydroxy groups occupying two distinct positions and C-C-N-O torsion angles of approximately 0 and 180 degrees for the two alternatives. This disorder, even though the site-occupancy factor of the less occupied position is as low as ca 0.06, is also observed at lower temperatures, which seems to favour the statistical and not the dynamic nature of this phenomenon.

2,6-Bis(3-fluoro-phen-yl)-3-isopropyl-piperidin-4-one.

In the title compound, C(20)H(21)F(2)NO, the piperidine ring in each of the two independent mol-ecules in the asymmetric unit adopts a normal chair conformation with an equatorial orientation of the 3-fluoro-phenyl groups. The dihedral angles between the two 3-fluoro-phenyl rings are 49.89 (7) and 50.35 (7)° in the two mol-ecules.

1-Chloro-acetyl-2,6-bis-(2-chloro-phen-yl)-3,5-dimethyl-piperidin-4-one oxime.

In the title compound, C(21)H(21)Cl(3)N(2)O(2), the piperidine ring adopts a distorted boat conformation. One of the chloro-phenyl rings is almost perpendicular to the best plane through piperidine ring, making a dihedral angle of 88.7 (1)°, whereas the other ring is twisted by 71.8 (1)°. The crystal packing is stabilized by inter-molecular C-H⋯O, C-H⋯Cl and O-H⋯O inter-actions.

1-Chloro-acetyl-2,6-bis-(2-chloro-phen-yl)-3,5-dimethyl-piperidin-4-one.

In the title compound, C(21)H(20)Cl(3)NO(2), the piperidin-4-one ring adopts a boat conformation. The two 2-chloro-phenyl groups are approximately perpendicular to each other, making a dihedral angle of 74.07 (8)°.

Crystal structure, DFT and Hirshfeld surface analysis of (E)-N'-[(1-chloro-3,4-di-hydro-naph-thal-en-2-yl)methyl-idene]benzohydrazide monohydrate.

In the title compound, C18H15ClN2O·H2O, a benzohydrazide derivative, the dihedral angle between the mean plane of the di-hydro-naphthalene ring system and the phenyl ring is 17.1 (2)°. In the crystal, O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds link the benzohydrazide and water mol-ecules, forming a layer parallel to the bc plane. Hirshfeld surface analysis and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H⋯H (45.7%) and H⋯C/C⋯H (20.2%) contacts.

Design, synthesis and biological evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents.

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one thiosemicarbazones (9-16) obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones (1-8) upon cyclization with ethylbromoacetate in the presence of sodium acetate-acetic acid buffer afforded novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones (17-24). The synthesized compounds have been characterized by their elemental, analytical and spectral studies. Besides, the reported compounds were screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies proved that compounds 11/18/20/23 against Staphylococcus aureus, 19/20/24 against Salmonella typhi show maximum inhibition potency at low concentration (6.25microg/ml) whereas 18/19 against Candida albicans and 19/20/21 against Rhizopus sp. showed beneficial antifungal activity at minimum concentration.

Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models.

The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflow calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (approximately 50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.

2-(2,4-Diphenyl-3-aza-bicyclo-[3.3.1]nonan-9-ylidenehydrazono)-1,3-thia-zolidin-4-one.

In the title compound, C(23)H(24)N(4)OS, the piperidine and cyclo-hexane rings adopt twin chair conformations and the phenyl groups occupy equatorial positions. The dihedral angle between the two benzene rings is 10.25 (12)°. The crystal structure is stabilized by intermolecular N-H⋯O hydrogen bonds with the formation of centrosymmetric dimers.

2,4-Bis(4-chloro-phen-yl)-3-aza-bicyclo-[3.3.1]nonan-9-one.

In the mol-ecular structure of the title compound, C(20)H(19)Cl(2)NO, the mol-ecule exists in a twin-chair conformation with equatorial dispositions of the 4-chloro-phenyl groups on both sides of the secondary amino group; the dihedral angle between the aromatic ring planes is 31.33 (3)°. The crystal structure is stabilized by N-H⋯O inter-actions, leading to chains of molecules.

Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents.

Structural based molecular docking approach revealed the findings of 2-(phenoxymethyl) -5-phenyl-1,3,4-oxadiazole derivatives. The compounds (7a-o) were synthesized and characterized well by using conventional methods. The compounds, 7b and 7m were reconfirmed through single crystal XRD analysis. The synthesized compounds (7a-o) were evaluated their antiproliferative activities against MCF-7 and MDA-MB-453. Furthermore, Lipinski's rule of five and pharmacokinetic properties were predicted for the test compounds. These results demonstrate that the compounds 7b and 7d exhibit more potent cytotoxicity and 7d exhibits dose-dependent activity and reduced cell viability. Further, the mechanism of action for the induced apoptosis was observed through morphological changes and western blotting analysis. These findings may furnish the lead for further development.

In silico Molecular Modelling of Selected Natural Ligands and their Binding Features with Estrogen Receptor Alpha.

BACKGROUND: Breast cancer is one of the most common cancers diagnosed among women. It is now recognized that two receptors mediate estrogen action and the presence of estrogen receptor alpha (ERα) correlates with better prognosis and the likelihood of response to hormonal therapy. ERα is an attractive target for the treatment of breast cancer. Most of the drugs currently used for the breast cancer treatment have numerous side effects and they are often unsuccessful in removing the tumour completely. Hence, we focused on natural compounds like flavonoids, polyphenols, etc. which do not exhibit any high toxic effects against normal cells. OBJECTIVES: To identify the potential natural inhibitors for BCa through an optimised in silico approach. METHODS: Structural modification and molecular docking-based screening approaches were imposed to identify the novel natural compounds by using Schrödinger (Maestro 9.5). The Qikprop v3.5 was used for the evaluation of important ADME parameters and its permissible ranges. Cytotoxicity of the compounds was evaluated by MTT assay against MCF-7 Cell lines. RESULTS: From the docking studies, we found that the compounds, Myricetin, Quercetin, Apigenin, Luteolin and Baicalein showed the highest Glide Scores -10.78, -9.48, -8.92, -8.87 and -8.82 kcal mol-1 respectively. Of these, Luteolin and Baicalein showed the significant IC50 values (25 ± 4.0 and 58.3 ± 4.4 µM, respectively) against MCF-7 cell line. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. CONCLUSION: We mainly focused on in silico study to dock the compounds into the human estrogen receptor ligand binding domain (hERLBD) and compare their predicted binding affinity with known antiestrogens. Myricetin, Quercetin, Apigenin, Luteolin and Baicalein were identified as the most promising among all. Of these, Luteolin and Baicalein showed significant anticancer activities against MCF-7 cell line. These findings may provide basic information for the development of anti-breast cancer agents.