Preparation and physicochemical characterization of N-succinyl chitosan-coated liposomes for oral delivery of grape seed extract and evaluation of its effect on pulmonary fibrosis induced by bleomycin in rats.

Objectives: This study aimed to develop an oral succinyl chitosan-coated liposomal formulation containing grape seed extract and assess its therapeutic efficacy in rats with bleomycin-induced pulmonary fibrosis. Materials and Methods: N-succinyl chitosan was synthesized, and the liposomal formulations were prepared and characterized regarding phenolic content assay and morphology. Size, zeta potential, in vitro drug release, and stability. Pulmonary fibrosis was induced by intratracheal bleomycin injection, and hydroxyproline measurements, lung weight, animal body weight, as well as histopathological studies were performed. Results: Succinyl chitosan increases the physical stability of the formulation, especially in acidic conditions. Drug release studies revealed that 66.27% of the loaded drug was released from CF2 in an acidic medium in 2 hr, but 92.31% of the drug was released in 8 hr in a pH=7 medium. An in vivo study demonstrated that rats exposed to bleomycin significantly lost weight, while those treated with CF2 (400 mg/kg) partially regained weight. Bleomycin treatment increased the mean lung weight and the amount of hydroxyproline in the lungs; these values were significantly decreased in the group treated with 400 mg/kg CF2 (P<0.05). Histopathological examination confirmed that treatment with 400 mg/kg CF2 improved lung fibrosis. Conclusion: In rats, oral administration of N-succinyl chitosan-coated liposomes containing grape seed extract at the 400 mg/kg dose ameliorates bleomycin-induced pulmonary fibrosis.

Novel Hydrazone Derivatives of 3-Bromopyruvate: Synthesis, Evaluation of the Cytotoxic Effects, Molecular Docking and ADME Studies.

A series of 3-bromopyruvate (3-BP) derivatives were synthesized to develop new potent anticancer agents. The chemical structures of the compounds were characterized using FT-IR, 1 H-, 13 C-NMR spectroscopy, and elemental analysis (CHN). Their cytotoxic activities were investigated against four cancer cell lines, including colon (SW1116), breast (MDA-MB-231), lung (A549), and liver (HepG2) cancer cell lines. Among the synthesized compounds, 3b showed promising cytotoxic activity compared to 3-BP, with IC50 values of 16.3 µM, 19.1 µM, 27.8 µM, and 14.5 µM against A549, MDA-MB-231, SW1116 and, HepG2 cell lines, respectively. Furthermore, the effect of these compounds on MCF-10A (a normal breast cell lines) was investigated to determine their selectivity between tumorigenic and non-tumorigenic cells. Since the 3-BP inhibits hexokinase II (HK II), molecular docking of 3-BP derivatives was carried out using AutoDock 4.2. The binding energies of these derivatives were greater than 3-BP, indicating that they had a higher affinity for HK II. For validation of docking, a 40 ns MD simulation was performed. SwissADME was used to predict pharmacokinetics, drug-likeness, and ADME parameters of the screened compounds. The results demonstrated that these derivatives are suitable candidates for developing orally potent HK II inhibitors.

3-Hydroxypyrimidine-2, 4-dione Derivatives as HIV Reverse Transcriptase-Associated RNase H Inhibitors: QSAR Analysis and Molecular Docking Studies.

AIDS, as a lethal disease, is caused by infection with the HIV virus that affects millions of people. Three essential enzymes should be encoded for replication of HIV virus: protease, integrase and reverse transcriptase (RT). RT has two different activities including DNA polymerase and ribonuclease H (RNase H). However, all of the marketed RT inhibitors target only the DNA polymerase activity. Therefore, ribonuclease H activity may serve as a new target for drug discovery. In the present study, a series of 3-Hydroxypyrimidine-2, 4-dione derivatives as potent RT-associated RNase H inhibitors were applied to QSAR analysis. Two methods including multiple linear regressions (MLR) and partial least squared based on genetic algorithm (GA-PLS) were utilized to find the relationship between the structural feathers and inhibitory activities of these compounds. The best multiple linear regression equation was generated by GA-PLS method. A combination of 2D autocorrelations, topological, atom-centered, and geometrical descriptors were selected by GA-PLS as they had more effects on the inhibitory activity. Then, the molecular docking studies were carried out. The results showed that the important amino acids inside the active site of the enzyme responsible for essential interactions were Gln475, Asp549, Tyr501, Ser515, Trp534, Asp493, Tyr472, and Gln480 which took part in hydrogen bond formation. Furthermore, docking energy was plotted against pIC50 predicted by GA-PLS method. The result showed that there is a good correlation with R2=0.71. Consequently, these findings suggest that the better method, GA-PLS, could be applied to design new compounds and predict their inhibitory activity.

Alignment-independent 3D-QSAR and molecular docking studies of tacrine-4-oxo-4H-Chromene hybrids as anti-Alzheimer's agents.

A series of novel tacrine derivatives as multifunctional agents with potential inhibitory effects on both acetylcholinesterase(AChE) and butyrylcholinesterase (BuChE) enzymes for the treatment of Alzheimer's disease(AD), were applied to alignment independent 3D-QSAR methods using Pentacle software. In this studies, GRID-independent molecular descriptors (GRIND) analysis have been applied to characterize important interactions between enzymes and the studied compounds. Two H-bond acceptor groups as well as hydrophobic properties of tacrine rings for AChE and two H-bond acceptor on the carbonyl group of chromene and NH of amid group for BuChE, with positive effects on their inhibitory potency have been identified. The obtained 3D-QSAR models have been analyzed and validated. The statistical quality of the QSAR model for AChE, r2 = 0.87, q2 = 0.56 and for BuChE, r2 = 0.96, q2 = 0.70 was resulted. Using these models, novel structures have been designed and pIC50 of them were predicted. Molecular docking studies were also conducted on AChE (1ACJ) and BuChE (4BDS) and promising results in good agreement with 3D-QSAR studies were obtained.

Synthesis, cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents.

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC50 of 6.65, 8.44 and 24.71 µM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.

Multitarget Drug Design, Molecular Docking and PLIF Studies of Novel Tacrine-Coumarin Hybrids for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) as a complicated and progressive neurodegenerative disorder is the most common form of dementia and memory loss. On account of the multifactorial etiology of AD, the multi-target-directed ligand (MTDL) approach is a promising method in searching new drug candidates for this disease. Here, in this paper more than 500 tacrine-coumarin hybrids have been designed and drug-likeness, molecular docking and descriptor analysis of them were performed to find out a drug candidate with less toxicity and better binding affinity than tacrine. The docking analysis was carried out using human acetylcholineesterase (1ACJ), human butyrylcholineesterase (4BDS) and ß-secretase (BACE1) (1W51) enzymes using AutoDock 4.2 and Vina. The promising results were obtained on the types of interactions. Based on docking on three targets and PLIF studies, the compounds that have better results were introduced as good candidates for synthesis. The validity of docking protocols was verified using a set of known active ligands and decoys on these targets.

One-Pot Green Regioselesctive Synthesis of γ-Lactones from Epoxides and Ketene Silyl Acetals Using 1,3-Dimethylimidazolium Fluoride as a Recoverable Metal-Free Catalyst.

In a straightforward and fast protocol, a mixture of 1,3-dimethylimidazolium fluoride ([DMIM]F) and 1-butylimidazolium tetrafluoroborate ([Hbim]BF4) efficiently catalyzed the reaction of epoxides with ketene silyl acetals (KSA) to give various γ-lactones under metal-free conditions. Diverse kinds of the desired γ-lactones were directly prepared with high regioselectivities and yields in a simple one-pot procedure using [DMIM]F as Si-O bond activator and [Hbim]BF4 as solvent and acidic ionic liquid catalyst. The ionic liquid mixture was recovered and reused three times and no loss in its activity was observed.

Enhanced photocatalytic degradation of tetracycline and real pharmaceutical wastewater using MWCNT/TiO2 nano-composite.

Photocatalytic degradation of tetracycline using MWCNT/TiO2nanocomposite was investigated under UVC irradiation. The effective operational parameters included pH, irradiation time, photocatalyst dosage, weight ratio of MWCNT to TiO2 and tetracycline concentration and were studied consecutively. Complete removal of tetracycline concentrations of up to 10 mg/L was obtained at MWCNT to TiO2 ratio of 1.5 (w/w%), pH 5, photocatalyst dosage of 0.2 g/L. Pseudo-first order kinetic model was best fitted with the experimental results (R2: 0.91-0.98 for different tetracycline concentrations). Based on TOC analysis, mineralization was 37% in the same reaction conditions for initial tetracycline concentration of 10 mg/L and reached to 83% after 300 min. In the case of real pharmaceutical wastewater, the COD concentration of 2267 mg/L decreased to 342 mg/L after 240 min in the same operational conditions.

Marine Sponge/H3PO4: As a Naturally Occurring Chiral Catalyst for Solvent-free Fischer-Indole Synthesis.

BACKGROUND: A new and efficient method have been developed for the synthesis of different indole derivatives from various ketones, having at least one hydrogen atom attached to each of their α-carbon atoms, and hydrazines in solvent-free conditions, using marine sponge/H3PO4 as a naturally occurring chiral catalyst. OBJECTIVES: This study recommended the use of marine sponge/H3PO4 as a naturally occurring chiral catalyst for preparation of phenylhydrazones from ketones having one α-hydrogen and subsequent cyclisation of the products to indoles. MATERIALS AND METHODS: The reaction was carried out by mixing the phenylhydrazine, ketone, and marine sponge/H3PO4 powder in mortar and pestle; the mixture was ground at room temperature in an appropriate time until TLC show the completion of the reaction. The product extracted by CH2Cl2 and evaporation of solvent yields the products. RESULTS: In this research work, several indoles are synthesized using phenylhydrazine and aliphatic or aromatic ketone as starting materials, in the presence of marine sponge/H3PO4 powder as a natural catalyst under solvent-free condition. CONCLUSIONS: We found marine sponge/H3PO4 to be an effective catalyst for indolisation of phenylhydrazones from ketones having α-hydrogens in solvent-free conditions.

Marine Sponge/CuO Nanocrystal: A Natural and Efficient Catalyst for Sulfonamides Synthesis.

BACKGROUND: Marine sponge/nano-CuO as a natural catalyst efficiently catalyzed the Sulfonylation reaction of p-chlorobenzene sulfonyl chlorides with amines in order to prepare sulfonamides. The advantages included use of a natural catalyst, ease of handling, requirement of a very small amount of catalyst, mild reaction condition and appropriateness to high yield. OBJECTIVES: The current study aimed to look for a solid support reaction and to develop a general, mild and novel method in order to synthesize sulfonamides in the absence of a strong base, it was found that marine sponge/nano-CuO is a natural and efficient catalyst for this method at room temperature. MATERIALS AND METHODS: The reaction was carried out simply by addition of amine and p -chlorobenzene sulfonyl chloride to the mixture of Marine sponge powder/nano-CuO in acetonitrile at room temperature. Then the reaction mixture was extracted by CH2Cl2 and was dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded the products. RESULTS: In this method several derivatives of sulfonamide underwent the reaction of different amines with p-chlorobenzene sulfonyl chloride in the presence of marine sponge/nano-CuO in CH3CN are synthesized. CONCLUSIONS: In conclusion, a new, natural and efficient marine catalyst, and a marine sponge/nano-CuO were developed to synthesize sulfonamide derivatives in CH3CN in 75-93% yields. This method was applied to a wide range of aromatic and aliphatic amines under mild conditions.