Letters in Drug Design & Discovery - Volume 7, Issue 10, 2010

In vitro radical-cation scavenging capacity and anti-AChE activities of 19 piperidine derivatives, including dihydrospiro[ piperidine-4,2'(1'H)quinolines] 7-19 and their precursor 4-allyl-4-arylaminopiperidines 1-6 were reported. Their data of bioassays and calculated logP and TPSA parameters showed promising drug-like properties. The best radical scavenging compound (TEAC 1.73 ± 0.01), 6-methyl-3',4'- dihydrospiro[piperidine-4,2'(1'H)quinoline] 8 showed IC50 value of 62.5 μM (20.0 μg/mL) using AChE assay.

A series of different Schiff bases of isatin 1-20 was synthesized by the condensation of isatin with primary aromatic amines. It was observed that some of these compounds have the potential to inhibit acetylcholinesterase, whereas some others showed specific activity against butyrylcholinesterase, depending upon substitution on the aromatic ring. Compounds 9 and 20 showed weak acetylcholinesterase inhibitory activity having IC50 values 28.3 ± 0.26 and 159 ± 2.9 μM, respectively. Nonetheless, compounds showed a varying degree of activity against butyrylcholinesterase with IC50 values in the range of 2.8 ± 0.07-82.9 ± 2.2 μM. Compounds 5, 2, and 11 showed IC50 values 2.8 ± 0.07, 5.2 ± 0.10, and 8.1 ± 0.30 μM, respectively, Their activity was compared with standard inhibitor galanthamine IC50 = 0.5 ± 0.01 μM for acetylcholinesterase and IC50 = 8.5 ± 0.01 μM for butyrylcholinesterase, respectively. The structures of all the synthesized compounds were confirmed by spectroscopic analysis.

Fourteen 4-Aryl-4H-chromeno[4,3-d][1,2,3] selenadiazole derivatives were synthesized by the reaction of flavonone- 4-semicarbazones with SeO2. The structures of the target compounds 1a-n were elucidated by 1H NMR, IR spectra, ESI-MS and elemental analyses. The preliminary cytotoxic activities of 1a-n against K562, KB, A549, SMC-7721 and SGC-7901 cell lines were evaluated by MTT method, indicating that most compounds displayed moderate to good antiproliferative activities against K562 and KB cell lines. Compounds 1m and 1n, the most potent ones, were promising template for development of novel potent antitumor agents.

The anticancer activity of Ocimum basilicum extract and its fractions was evaluated using human cancer cell lines; active compound(s) residing in it were identified and mechanism of their anti-proliferative action was explored. Methanolic extract was fractionated into petroleum ether soluble (PE-S) and insoluble (PE-I) fractions. These were evaluated on HT-144, MCF-7, NCI-H460 and SF-268 cell lines using Sulforhodamine B assay. Immunofluorescence microscopy was employed to study their effects on the cytoskeleton and nuclei of MCF-7 cells. Fractionation of PE-I (GI50: 5 μg/ml; LC50: 71μg/ml against MCF-7) led to the isolation of four compounds, mainly ursolic acid (LC50: 18.6 μg/ml). Ursolic acid (100 μM) induced a significant decrease in the percentage of cells in anaphase/telophase stages along with F-actin aggregation and mitotic spindle distortion. These results support anti-proliferative activity of O. basilicum extract against MCF-7 cells which may partly be due to effects of ursolic acid on F-actin and microtubules.

Eight new 4-alkyl/aryl-1-(3-phenoxypropionyl)-thiosemicarbazides were synthesized by condensation of 3- phenoxypropionic acid hydrazide with related isothiocyanates. All compounds were tested in vitro for their antibacterial and antifungal activity. One compound, 4-(4-chlorophenyl)-1-(3-phenoxypropionyl)-thiosemicarbazide, showed high level of activity against Gram-positive species, MICs range 12.5-50 μg/mL. Semiempirical calculations of geometries, energies, and QSAR parameters have been determined in hope to get insight into different biological activity of closely related isomers.

The 1,3-dipolar cycloaddition of N-aryl-C-ethoxycarbonylnitrile imines to pyridazin-3-thione afforded novel spirothiadiazolopyridazines in moderate to good yields. The reaction occurs regioselectively at the exocyclic C=S bond. Some of the newly synthesized compounds were tested for their in vitro antitumor activity against three human and murine cell lines [human: A2780, (ovary, carcinoma), A549 (lung, carcinoma); murine: P388 (leukaemia)]. Among the series, some compounds exhibited significant growth inhibitory effects against cell lines P388.

16 ADT carboxylate esters were prepared and tested for their chemical characteristics, stability, bioavailability, potency and toxicity. Considering the good bioavailability, 3a was selected for the pharmacology test, and the result showed that the potency of 3a was remarkably higher than that of ATT. Additionally, 3a was also chosen for the acute toxicity test. The result indicated that the prodrug 3a was more safer than ATT. The study suggested the feasibility to improve the bioavailability of ATT by using prodrug strategy.

A series of 48 commercial benzaldehydes have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv, using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Benzaldehydes 39 and 41 exhibited a significant activity at 3.12 μg/mL. Although commercial benzaldehydes have been largely used by many research groups in search of news TB-drugs, they had not been tested previously against Mycobacterium tuberculosis. This study adds important information to the rational design of new lead anti-TB drugs.

A high initial burst release of an antisense oligonucleotides drug from poly(lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) method was significantly reduced, when the microparticles were treated with a polymer non-solvent (ethanol)/water mixture. The ethanol/water mixture acted like a plasticizer and significantly decreased the glass transition temperature (Tg) of the PLGA. Thus, PLGA microparticles in the wet state became soft, and the surface pores were fused together during treatment. As a result, microparticles with reduced surface pores that released a low initial burst were obtained. The reduction in the initial burst was more significant for the smaller microparticles (<50 μm) and decreased with increasing microparticle size. A less significant reduction in the initial burst was observed when the microparticles were treated with a polymer solvent (e.g., acetone)/water mixture.

The recently introduced concept of “interactomics” or “associomics” - defined as the complete repertoire of physical protein-protein interactions (PPIs), ranging from temporary (co-expression of interacting proteins), spatial (cell compartment or specific cell-type existence), conditional (disease-health state) or transient functional pairings to the formation of stable, permanent complexes - presents us with a variety of technical research challenges. Its main bottleneck, however, remains the restricted number of currently available high-throughput screening (HTS) techniques capable of PPI detection. One of the most popular and effective methods is in this context the yeast two-hybrid (Y2H) system which has (despite some undeniable practical limitations) been used in thousands of experimental settings, accounting for the majority of all published PPI data. Therefore, this mini-review summarizes the basic principles and most valuable modifications that have been developed since the introduction of the Y2H system by Fields and Song 20 years ago, and describes its recent expansion towards automation and high-throughput application obligatory for the global investigation of the eukaryotic proteome. Finally, we take a close look at a choice of currently available large-scale analytical strategies (with special emphasis on the human interactome) some of which have already culminated in comprehensive, partly interconnected maps, but which are, nevertheless, still too incomplete to assemble a true picture of all physiologically significant PPIs within the living cell. For this reason, the HTS upgraded Y2H system - in combination with other approaches - will continue to provide an essential tool for the detailed dissection and further characterization of proteome-wide PPIs on a systems biology scale.