Letters in Drug Design & Discovery - Volume 12, Issue 6, 2015

An efficient method for the synthesis of various primary and secondary amines through a zirconium(IV) isopropoxide–mediated reductive amination reaction of aldehydes and ketones is reported. A series of different aldehydes, ketones and amines were used leading to the expected amino products in moderate to excellent yields. The mechanistic rationale of this reaction has been postulated through the formation of a transient imine species and a diastereoselective version using (R)- phenylethylamine as chiral inducer led to the expected products in moderate to excellent yields and with diastereoselectivities up to 100%.

We report a FeCl3•6H2O mediated green and rapid access to benzothiazole derivatives having a substituent at C-2 via the condensation of 2-aminothiophenol with various aldehydes under ultrasound irradiation and air. The reaction progressed well in water affording the expected products in good yields. Two of these compounds known to be potent anticancer agents showed good interactions with PDE4B in silico and inhibited this enzyme when tested in vitro.

Some phenylalanine (Phe) derivatives had important roles in pharmacology and may be used as pharmaceutical materials and pharmaceutical intermediates. In order to understand the cell toxicity of phenylalanine derivatives, we synthesized L-4-bromo-phenylalanine (Brp), L-4-iodophenylalanine (Ip), L-4-nitro-phenylalanine (Np), L-4-sulfonic-phenylalanine (Sp), L-4-phosphophenylalanine (Pp) and L-4-amino-phenylalanine (Np). We used mass spectrometry (MS), Infrared Spectroscopy (IR) or hydrogen-1 nuclear magnetic resonance spectrum (1H-NMR), and high performance liquid chromatography (HPLC) to test the correction of these products, MTT assay and Hoechst33258 staining to detect their cell toxic effect on human colon cancer cell HT-29 (HT-29 cells). The results showed that these products were correct and the cytotoxicity of Pp>Ip>Sp and Np>Brp, Ap almost had no effect on HT-29 cells. In addition, Pp, Ip and Sp induced cell apoptosis, the other three kinds of phenylalanine derivatives induced neither apoptosis nor necrosis.

6-Amino-1, 3-dimethyl-1H-pyrimidine-2, 4-dione 2 was prepared by alkylation of 6-amino- 1H-pyrimidine-2, 4-dione 1 with methyl iodide. Formylation of 2 with formic acid afforded N-(1, 3- dimethyl-dioxo-tetrahydropyrimidin-4-yl)-formamide 3. The nitration of 3 gave N - (1,3-dimethyl-5- nitro-dioxo-tetrahydropyrimidin-4-yl) formamide 4. Reduction of 4 by zinc dust in glacial acetic acid yielded dimethyl-dihydro-purine-2, 6-dione 5. Addition of bromine to 2 leads to the formation of 6- amino-5-bromo-dimethyl-pyrimidine-2, 4-dione 7, cycloaddition of 7 with formamide afford the same product (theophylline 5), alkylated of 5 with methyl iodide to give caffeine 6. Reaction of 7 with glycine gave 2-(6-amino-dimethyl-dioxo-tetrahydropyrimidin-5-ylamino) acetic acid 8, refluxing of 8 with acetic acid /methanol gave dimethyl-dihydropyrimidopyrazine-trione 9, alkylation of 9 with alkyliodide afforded tetra-alkyldihydropyrimidopyrazine- trione 10a and 10b. The Cytotoxicity screen of the synthesized compounds was evaluated and the result showed that 10a, 10b, 9, 8, 7 and 6 exhibited highly potential antitumor activity.

Dipeptidyl peptidase IV (DPP-IV) is an attractive target, and its launched inhibitors have made great significance to clinical therapy of type 2 diabetes. For developing high potent DPP-IV inhibitors, ligand- and structure-based approaches were applied for the optimization of cyanopyrrolidine in this study. Two statistically significant 3D-QSAR models (CoMFA with q2, 0.585; r2, 0.963; CoMSIA with q2, 0.678; r2, 0.949) were developed. In combination with the structure-based pharmacophore model, fundamental structural requirements and pharmacophoric features for R groups were determined. Suitable fragments for different R groups were retrieved for the generation of novel molecules. After being evaluated by molecular docking, QuaSAR descriptors filter and 3D-QSAR activity prediction, active DPP-IV inhibitors were found. The reliability indicated this workflow can be applied to facilitate lead optimization for DPP-IV and even for other drug targets.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition is thought to be an encouraging approach towards the therapy of Alzheimer’s disease (AD). The current paper targets to give a concise information of mono and dihalo- substituted thioureas similarity with anti-AD potential. The present results represent evaluation of cholinesterase inhibitory potential for halogenated thioureas derivatives. Compound 1t was constituted to be highly potent inhibitor with Ki value 0.12 ± 0.05 µM against AChE, while 1b was most the active inhibitor for BChE with Ki value of 0.03 ± 0.001 µM. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the plausible binding modes of synthesized compounds.

A new class of 1, 3, 4-oxadiazoles substituted stearic/palmitic acid analogues were prepared. In-silico docking studies have been done into the crystal structure of thioesterase domain of human fatty acid synthase (2PX6) that gave some important structural information on the ligand binding interactions. The residues His 2481, Tyr 2462 & Ala 2448 formed hydrogen bonds with 1, 3, 4–oxadiazole ring. All the target compounds exhibited good binding interactions with the active site residues. Cytotoxicity has been done for some selected compounds against human lung carcinoma cell lines (A-549) by SRB method. The compounds showed strong cytotoxicity.

Two series of 6-(4-Cl-Phenyl)-4-arylidene-4,5-dihydropyridazin-3(2H)-one (3a-e) and 6- (4-CH3-Phenyl)-4-arylidene-4,5-dihydropyridazin-3(2H)-one derivatives (3f-j) were synthesized and evaluated as antitubercular agents against Mycobacterium tuberculosis H37Rv strain by using Microplate Alamar Blue Assay (MABA) method. These compounds (3a-e & 3f-j) were synthesized from 6-(4-Cl-Phenyl)-4,5-dihydropyridazin-3(2H)-one (2a) and 6-(4-CH3-Phenyl)-4,5-dihydropyridazin- 3(2H)-one (2b) compounds by reacting with appropriate aldehydes respectively. All title compounds (3a-e & 3f-j) were characterized on the basis of IR, 1HNMR, mass spectral and elemental analysis data. All title compounds (3a-e & 3f-j) were used at 0.2µg/mL to 100µg/mL dose levels for antitubercular activity. Result showed that all the title compounds (3a-e & 3f-j) exhibited less antitubercular activity as compared to the reference drugs streptomycin (MIC value of 6.25µg/mL) and pyrizinamide (MIC value of 3.125µg/mL), except compound 3e, which was equally effective as streptomycin but less effective than pyrazinamide.

Aryl esters of 1,1’-bis(4-hydroxyphenyl)cyclohexane (bisphenol-C) were synthesized by condensing bisphenol-C with aryl acid chlorides using triethylamine as a catalyst and ethyl acetate as a solvent at room temperature.The compounds were characterized by FTIR, 1HNMR, 13CNMR and MS; and assayed for their antibacterial activity against S. aureus MTCC-96, B. subtilis MTCC-441, E. coli MTCC-443, S. typhi MTCC-98 and antifungal activity against A. niger MTCC-282 and A. clavatus MTCC-1323 and compared with standard drugs. The minimum inhibition concentration (MIC) of the compounds was studied by micro broth dilution method. 1a-f and 2a-f showed moderate to comparable antibacterial activity against E. coli, S.typhi, B. subtillis and S. aureus. All the compounds did not show antifungal activity. Methyl side substituent and aromatic ring affected considerably antibacterial activity.

Novel macroporous composite hydrogels were synthesized by free radical polymerization of crylic acid (AA), chitosan (CS) and beta-cyclodextrin (β-CD) with N,N-methylenebisacrylamide (MBA) as the cross-linking agent. The structure of the resultant hydrogels was characterized by the Fourier Transform Infrared Spectrum (FT-IR) spectroscopy and Scanning Electron Microscopy (SEM). The thermal stability was also investigated by thermal gravimetric analyzer. The swelling properties were investigated in detail. The results revealed that the prepared hydrogels exhibited high pH sensitivity and well reversible property by undergoing a number of swelling/de-swelling recycles. Nicotinamide was chosen as a model drug to evaluate the controlled drug release behavior. The results indicated that the release rate decreased with the increasing of β-CD content in acidic solution (pH=1.80).