Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities.

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.

Bromination and conversion of tetrahydro-1H-indene to bisoxirane with a new approach: synthesis, structural characterization by spectroscopic and theoretical methods, and biological analysis supported by DFT and docking.

In this study, a new method for synthesizing diepoxides is proposed. Tetrahydroindene 1 was brominated with NBS in the presence of LiClO4 and acetic acid, resulting in the formation of dibromodiacetate derivatives 2 and 3. Treatment of compounds 2 and 3 with NaOH in methanol produced a mixture of diepoxides 4 and 5. Additionally, direct bromination of tetrahydro-1H-indene yielded tetrabromo octahydroindene isomers 6 and 7. The structures of the compounds were characterized using spectroscopic techniques such as 1H NMR, 13C NMR, APT, COSY, and XRD. The new method provides an easy and selective route to access epoxides for the synthesis of various chemicals. This study also highlights the selective formation of endo-exo and exo-exo orientations of the obtained diepoxides, distinguishing it from previous studies. The stability and properties of the stereoisomers were investigated using computational methods, revealing the most stable configurations. Reactive sites in the molecules were identified using contour diagrams and molecular electrostatic potential maps. The anticancer properties of the compounds were evaluated in silico, comparing them to 5-fluorouracil (5-FU) against several cancer cell lines. The compounds exhibited the most effective anticancer activity against MCF-7 cells, with the order of anticancer activities generally determined as 2 > 7 > 3 > 6 > 5 > 4 > 5-FU.

High-Performance Material for the Effective Removal of Uranyl Ion from Solution: Computationally Supported Experimental Studies.

Adsorption is a widely used method for pollution removal and for the recovery of valuable species. In recent years, the use of metal-organic compounds among the adsorbents used in adsorption studies has increased. In this study, the performance of the water-insoluble Fe complex as a metal organic framework (MOF-Fe-Ta) of water-soluble tannic acid, which is not used as an adsorbent in uranium recovery and removal, was investigated. For the characterization of the new synthesized material, Fourier transform infrared, scanning electron microscopy, and X-ray diffraction analyses were performed. The changes in the adsorption process based on various parameters were investigated and discussed. The point of zero charges value of the adsorbent was found as 5.52. It was noticed that the adsorption increases as the pH increases. Analyzing the effect of concentration on adsorption, we determined which model explained the adsorption better. The monolayer capacity of the adsorbent determined in light of the Langmuir model was reported as 0.347 mol kg-1. The Freundlich constant, namely the ß value obtained in the Freundlich model, which is a measure of surface heterogeneity, was found to be 0.434, and the EDR value, which was found from the Dubinin-Raduskevich model and accepted as a measure of adsorption energy, was 10.3 kJ mol-1. The adsorption was kinetically explained by the pseudo-second-order model and the adsorption rate constant was reported as 0.15 mol-1 kg min-1. The effect of temperature on adsorption was studied; it was emphasized that adsorption was energy consuming, that is, endothermic and ΔH was found as 7.56 kJ mol-1. The entropy of adsorption was positive as 69.3 J mol-1 K-1. As expected, the Gibbs energy of adsorption was negative (-13.1 kJ mol-1 at 25 °C), so adsorption was considered as a spontaneous process. Additionally, the power and mechanism of the interaction between studied adsorbent and adsorbate are explained through density functional theory computations. Computationally obtained data supported the experimental studies.

Design, synthesis, DFT calculations, molecular docking and antimicrobial activities of novel cobalt, chromium metal complexes of heterocyclic moiety-based 1,3,4-oxadiazole derivatives.

A Schiff base, 5-(4-methylphenyl)-4-[(pyridin-2-ylmethylidene)amino]-4H-1,2,4-oxadiazole as a bidentate ligand has been synthesized by the reaction between the 4-amino-5-(4-methylphenyl)-4H-1,3,4-oxadiazole and aromatic aldehyde. The Schiff base reacted with CoCl3·6H2O and CrCl3·6H2O in ethanol to yield 1,3,4-oxadiazole complexes. The structures of synthesized ligand and their complexes have been established on the basis of their IR, Mass and 1H-NMR spectra. Electronic and geometric structures of both cobalt and chromium complexes were investigated by density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations. DFT-based reactivity calculations estimated the studied system as strong electrophile and/or strong nucleophile in polar organic reactions. Moreover, most reactive sites were predicted theoretically based on the delocalized and localized indexes. The nature of Ligand-Metal chemical bonding is discussed in terms of the natural bond orbital (NBO) and QTAIM analysis. Accordingly, the metal ions such as cobalt and chromium are bidentate coordinated with the Schiff base by nitrogen atoms of imine function and pyridine, to form stable complexes. Furthermore, the chromium ions have an affinity superior to the cobalt ions towards Schiff base ligand. In addition, the results of the antibacterial activity in-vitro show that the metal complexation confers an increase in the antibacterial activity of the complexed ligand compared to the free ligand against both Gram-positive and Gram-negative bacteria with broad spectrum activity. In silico molecular docking studies of the ligands and their complexes were applied to describe the probable binding modes into the active site of Escherichia coli (E. coli) FabH and Salmonella typhimurium LT2 neuraminidase (STNA) receptors. The increase in biological activity could be attributed to the high stability of the complexes and strong affinities to bacterial enzyme receptors.Communicated by Ramaswamy H. Sarma.

Effect of fulvic acid on gastric mucosa damage caused by chronic water avoidance stress.

We investigated the antioxidant and anti-ulcerogenic effects of fulvic acid (FA) on oxidative damage caused by water avoidance stress (WAS) in rat gastrointestinal mucosa. Three experimental groups were established: control (C), chronic stress (CS), and chronic stress + FA (CS + FA). After WAS, a single dose of FA was administered for 10 days to the CS + FA group. Samples of the pyloric region of the stomach were stained with hematoxylin and eosin (H & E) and periodic acid-Schiff (PAS). Immunohistochemical staining was performed for inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) levels were measured biochemically. By light microscopy, we observed loss of gastric epithelial cells and greater polymorphonuclear cell migration into the mucosa in the CS group compared to the C group. We found intact epithelial cell structure and a thick superficial mucus layer in the CS + FA group compared to the CS group. These findings in the CS + FA group were similar to those for group C. iNOS staining was stronger in the CS group compared to the C group. TOS and OSI levels in the CS + FA group were decreased compared to the CS group, but TAS, SOD, GPx and CAT levels were increased. We found that WAS caused damage to epithelium and connective tissue of the stomach mucosa and that this damage was prevented by FA. Therefore, administration of FA appears to prevent stress induced damage to rat stomach.

Synthesis and some enzyme inhibition effects of isoxazoline and pyrazoline derivatives including benzonorbornene unit.

Four new and four known isoxazoline derivatives were synthesized from the reactions of benzonorbornadiene with nitrile oxides formed from the corresponding benzaldehydes. Three new and one known pyrazoline derivatives were also synthesized from the reactions of the benzonorbornadiene with nitrile imines formed from the corresponding compounds. The synthesized nitrogen-based novel heterocyclic compounds were evaluated against the human carbonic anhydrase isoenzymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The synthesized nitrogen-based novel heterocyclic compounds showed IC50 values in the range of 2.69-7.01 against hCA I, 2.40-4.59 against hCA II, 0.81-1.32 µM against AChE, and 20.83-1.70 µM against BChE enzymes. On the contrary, nitrogen-based novel heterocyclic compounds demonstrated Ki values between 2.93 ± 0.59-8.61 ± 1.39 against hCA I, 2.05 ± 0.62-4.97 ± 0.95 against hCA II, 0.34 ± 0.02-0.92 ± 0.17 nM against AChE, and 0.50 ± 0.04-1.20 ± 0.16 µM against BChE enzymes. The synthesized nitrogen-based novel heterocyclic compounds exhibited effective inhibition profiles against both indicated metabolic enzymes. These results may contribute to the development of new drugs particularly to treat some disorders, which are widespread in the world including glaucoma and Alzheimer's diseases.

Synthesis, characterization, and SAR of arylated indenoquinoline-based cholinesterase and carbonic anhydrase inhibitors.

We report the synthesis of bromoindenoquinolines (15a-f) by Friedlander reactions in low yields (13-50%) and the conversion of the corresponding phenyl-substituted indenoquinoline derivatives 16-21 in high yields (80-96%) by Suzuki coupling reactions. To explore the structure-activity relationship (SAR), their inhibition potentials to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase cyctosolic (hCA I and II) enzymes were determined. Monophenyl (16-18) indenoquinolines significantly inhibited the AChE and BChE enzymes in ranges of IC50 37-57 nM and 84-93 nM, respectively, compared with their starting materials 15a-c and reference compounds (galanthamine and tacrine). On the other hand, these novel arylated indenoquinoline-based derivatives were effective inhibitors of the BChE, hCA I and II, BChE and AChE enzymes with Ki values in the range of 37 ± 2.04 to 88640 ± 1990 nM for AChE, 120.94 ± 37.06 to 1150.95 ± 304.48 nM for hCA I, 267.58 ± 98.05 to 1568.16 ± 438.67 nM for hCA II, and 84 ± 3.86 to 144120 ± 2910 nM for BChE. As a result, monophenyl indenoquinolines 16-18 may have promising anti-Alzheimer drug potential and 3,8-dibromoindenoquinoline amine (15f) can be novel hCA I and hCA II enzyme inhibitors.

2,5-Dibromo-indan-1-ol.

In the title compound, C(9)H(8)Br(2)O, the cyclo-pentene ring adopts an envelope conformation with the brominated C atom as the flap. In the crystal, mol-ecules are linked by strong O-H⋯O hydrogen bonds into zigzag C(4) chains along [010]. In addition, a C-H⋯π inter-action involving the benzene ring and the H atom attached to the hy-droxy-lated C atom is observed.

2,4-Dibromo-2,3-dihydro-1H-inden-1-yl acetate.

In the title compound, C(11)H(10)Br(2)O(2), the cyclo-pentene ring fused to the benzene ring adopts an envelope conformation, with the C atom attached to the Br atom as the flap. The crystal structure does not exhibit any classical hydrogen bonds. The mol-ecular packing is stabilized by van der Waals forces and π-π stacking inter-actions with a centroid-centroid distance of 3.811 (4) Å.

2,3-Dihydro-1H-cyclo-penta-[b]naph-tha-len-1-ol.

In the title compound, C(13)H(12)O, the cyclo-pentene ring fused with the naphthalene group adopts an envelope conformation. The cyclo-pentene torsion angle, with the fusion bond at the centre, has a magnitude of 1.16 (16)°. In the crystal, neigh-bouring mol-ecules are connected through O-H⋯O hydrogen bonds into an R(4) (4)(8) ring motif. The crystal packing also features weak π-π stacking inter-actions [centroid-centroid distance = 3.8981 (8) Å] and C-H⋯π inter-actions.

5-Amino-4-bromo-2,3-dihydro-1H-inden-1-one.

In the title compound, C(9)H(8)BrNO, the non-H-atom framework is essentially planar, with a maximum deviation of 0.087 (3) Å. In the crystal, mol-ecules are inter-connected into a three-dimensional network by C-H⋯O and N-H⋯O hydrogen bonds. In addition, C-H⋯π inter-actions and a π-π stacking inter-action, with a centroid-centroid distance of 3.5535 (19) Å, are also observed.

Synthesis of new anthracene derivatives.

An efficient synthesis is described for hexabromoanthracenes 3 and 4 by direct bromination of 9,10-dibromoanthrecene 2. Whereas base-induced elimination of hexabromide 3 with t-BuOK gave 2,3,9,10-tetrabromoanthracene 5, the reaction of hexabromide 4 with DBU afforded 1,3,9,10-tetrabromoanthracene 6 as the sole product. Tetrabromide 5 was also obtained by aromatization of 1,4-dinitroxy-2,3,9,10-tetrabromo-1,2,3,4-tetrahydroanthracene 17. Efficient and convenient synthetic routes are described for the preparation of dinotroxy 17, dimethoxy 23, and dihydroxides 18 and 19 with silver-induced substitution of hexabromides 3 and 4. The hydroxy compounds 19 and 18 were converted to diepoxide 20 and monoepoxide 21, respectively, with sodium methoxide. Base-promoted aromatization of dimethoxide 23 afforded dibromomonomethoxides 26 and 27. Bromoanthracenes and isomeric arene oxides constitute valuable precursors for the preparation of functionalized substituted anthracene derivatives that are difficult to prepare by other routes.