Letters in Drug Design & Discovery - Volume 11, Issue 6, 2014

In this work the use of 2D atom-based quadratic indices is shown in the prediction of proteasome inhibition. Machine learning approaches such as support vector machine, artificial neural network, random forest and k-nearest neighbor were used as main techniques to carry out two quantitative structure-activity relationship (QSAR) studies. First, a database consisting of active and non-active classes was predicted with model performances above 85% and 80% in learning and test series, respectively. Second a regression-based model was developed which allow to estimate the EC50 with Q2 values of 52.89 and 50.19, in training and prediction sets, respectively, were developed. These results provided new approaches on proteasome inhibitor identification encouraged by virtual screenings procedures.

In the present study, a series of novel quinazolinones functionalized with urea/thiourea/thiazole derivatives was synthesized and evaluated for their antioxidant and 5-lipoxygenase (5-LOX) inhibition activities. The newly synthesized compounds were characterized using 1H NMR, 13C NMR, IR, Mass spectra and elemental analysis. The antioxidant activities of the title compounds were evaluated using DPPH, superoxide, hydroxyl and nitric oxide radical scavenging assay in vitro. It is revealed from the antioxidant screening results that the compounds 3e, 5f and 6c manifested profound antioxidant potential. The synthesized compounds were screened for their 5-LOX inhibitory activity. Overall, 3e, 5f and 6c showed promising antioxidant and 5f showed 5-LOX inhibitory activity and may be used as the lead compounds in the future study.

Soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators which are involved in the regulation of blood pressure and inflammation. Although the most reported potent sEH inhibitors are urea derivatives, these compounds have limited pharmacokinetic profile. In order to improve physicochemical properties, besides having favorable potency, amide non-urea derivatives with oxadiazole ring as a novel secondary pharmacophore against sEH enzyme were developed. Most of the novel compounds with appropriate physical properties, had comparable in vitro sEH inhibitory activity to 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a potent urea-based sEH inhibitor. The IC50 value of the most potent compound (15c) was 0.43 nM.

The development of antitumor drugs with novel effects is urgent for cancer patients. In our recent anticancer drug discovery study, 1,2-di(quinazolin-4-yl)diselane (LG003) was synthesized and showed considerable antitumor effects on six tested cancer cell lines in vitro. Morphological observation and Lactate Dehydrogenase release assay revealed that LG003 exerted such effect in A549 cells through antiproliferation, apoptosis or other pathway rather than cytotoxicity which suggests that compound LG003 is a potential antitumor agent.

A series of aryl benzyl ethers with fluoro substituents were synthesized and their structures were confirmed by spectral. All the compounds were tested for their cytotoxic activity in vitro against two human tumor cell lines: A549, SGC7901, and most showed cytotoxicity. Compound 10 was the most active in suppressing the growth of both screened cancer cells.

Four naphthalimide derivatives 2-5 modified with various alkylenediamines at 4-position have been designed and synthesized. Their anticancer activities were preliminarily evaluated, which showed potent anticancer activities against A549 cell line with IC50 values lower than 5 μM. Furthermore, the DNA binding properties of 2 with calf thymus (Ct) DNA were investigated by UV-Vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation experiment. The results showed that compound 2 as the DNA intercalator exhibited strong binding affinity with Ct- DNA.

Adenosine deaminase (ADA) inhibitors have been found to have antitumor activities. Here, thirteen potential adenosine deaminase inhibitors 5-amino-1H-pyrazole-4-carboxamide derivatives were designed, synthesized and screened for antitumor activities. Compound 8e exhibited strong growth-inhibitory effects which showed selectivity toward the estrogen receptor positive breast cancer cells (MCF-7) compared to other 5-amino-1H-pyrazole-4-carboxamide derivatives. In addition, it also exhibited appropriate (μM) adenosine deaminase inhibitory potency. Preliminary structure-activity relationships indicated that the incorporation of long chain branching on nitrogen atoms at pyrazole moiety was responsible for their activity.

A simple and facile route has been described for the synthesis of macrocyclic tetraamides. This method is applicable for the preparation of a variety of macrocyclic tetraamides of various heteroatom substitutions.

A series of N1-substituted 2,4,5-triphenyl imidazole derivatives was designed, synthesized and evaluated for their p53-MDM2 binding inhibitory activities and anti-proliferative activities in vitro against four human cancer cell lines (PC3, KB, A549 and HCT116). Although logical evaluation revealed weak p53-MDM2 binding inhibitory activities, most of the obtained molecules displayed moderate to potent cytotoxicities against tested cell lines. As a potential lead compound for further optimization, compound 9c was evaluated as the most potent compound against four cell lines and could induce cell cycle arrest at G2/M phase. The binding mode of compound 9f and MDM2 was further studied by docking analysis and the unexpected interaction mode revealed that this series of compounds may take part into a different binding modes as the lead compound Such as Nutlin, which could induce a different mechanism in cancer therapy.

2,5-[[(1,1-Dimethylethyl)oxidoimino]methyl]-3,6-trimethylpyrazine (TN-2), a novel derivative of tetramethylpyrazine (TMP), is effective in reducing brain infarct size in animal brain ischemia models. The purpose of this study is to evaluate its pharmacokinetic profiles including plasma pharmacokinetics, dose proportionality, tissue distribution, excretion in rats and protein binding ability in vitro. In doses ranging from 5 to 80 mg/kg, TN-2 displayed linear pharmacokinetic characteristics. After intragastric (i.g.) administration, it was absorbed rapidly and the maximum concentration (Cmax) was observed at 28.5 min. The absolute bioavailability was 69.3%. After intravenous (i.v.) injection, TN-2 distributed to various tissues rapidly. The area under curve (AUC) of TN-2 in brain tissues was 14% in plasma. Kidney was the main excretory organ where approximately 80% was excreted in the prototype form through urine. The protein binding rate was 3.4% and 12.5%, respectively, in plasma of rat and human.

Adenosine 5’-monophosphate (AMP) activated protein kinase (AMPK) is a highly conserved sensor of cellular energy. AMPK has been recognized as a key regulator of mammalian metabolic function and has emerged as an attractive target for the treatment of metabolic disorders, including obesity and type 2 diabetes. The synthesis and biological evaluation of novel 3-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)propanoic acid derivatives as AMPK activators are described. The in vivo proof of principle for plasma glucose lowering effect is exemplified with a lead compound from this series.

The rationale of this study was to investigate the effect of cyclodextrins (β-CD or HPβ-CD) on the dissolution of a poorly water soluble drug: Piroxicam (Px). Interactions of piroxicam (Px) and β-CD or hydroxypropyl-β-CD (HPβ- CD) have been investigated in solution and in the solid state. The phase solubility of inclusion complex for each CD was studied according to Higuchi and Connors method. Equimolecular (Px - β-CD) or (Px - HPβ-CD) solid systems were prepared using different techniques. Solubility studies demonstrated the formation of the (Px - β-CD) and (Px - HPβ-CD) inclusion complexes with 1:1 stoichiometry. In all cases, a significant increase in the dissolution rate with respect to the drug alone was evidenced, which was attributed to the formation of an inclusion compound. The dissolution performance of the complexes appeared to be related to both the preparation method of the solid system and the type of CD used. Among the solid complexes obtained either with β-CD or HPβ-CD, the freeze-dried and the spray-dried systems were the most effective in achieving the enhancement of the Px dissolution rate. The enhancement was better from HPβ-CD than β- CD except for the freeze-drying (P4.2) and the spray-drying methods. The characterization (DSC, TGA, FT-IR and PDRX) showed differences between the complexes and their corresponding physical mixture and individual components.

Induced fit docking approach was utilized to decipher the binding mode of the recently reported dibenz[b,f]1,5- oxazocine derivative having activity towards κ -Opioid receptor. The result of docking to newly resolved crystallographic structure of κ -Opioid receptor established the important interactions as two hydrogen bonds, a π-π interaction, and two hydrophobic interactions. Based on the study it is inferred that protonated nitrogen is not always essential for binding of non-peptidic nitrogen containing opioids to κ -Opioid receptor. Also, docking was performed using well-known kappa agonist pentazocine to prove different binding requirements of the dibenzo compound. A pharmacophoric model has been developed based on the previously known nitrogen containing κ -Opioid receptor agonists and the new dibenzo compound to determine the minimal 3D features, required for κ -Opioid agonist activity. To our knowledge, this is the first report of a binding mode analysis study for non-protonated nitrogen containing κ-Opioid receptor agonist.

In this study, we aimed at the synthesis of new 2-((5-substituted-4-methylthiazol-2-yl)amino)-2-oxoethyl 4- substitutedpiperazine-1-carbodithioate derivatives and their antibacterial, antifungal, antioxidant and AChE inhibitory evaluations. A set of fifteen new compounds of 2-((5-substituted-4-methylthiazol-2-yl)amino)-2-oxoethyl 4-substitutedpiperazine- 1-carbodithioate derivatives were synthesised by reacting 2-chloro-N-(5-substituted-4-methylthiazole-2- yl)acetamide derivatives and sodium salts of appropriate N-substitutedpiperazine dithiocarbamic acids in acetone. The chemical structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR, MS spectral data and elemental analysis. The antibacterial and antifungal activities of the synthesised derivatives were tested against Gram (+), Gram (-) bacteria and yeasts such as Salmonella typhimurium, Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Candida albicans, Candida utilis, Candida tropicalis, Candida krusei and Candida glabrata using a microbroth dilution technique. Antimicrobial results showed that the compounds displayed minimum inhibitory concentrations in the range of 15.62-4000 μg/mL. Antioxidant activity of the synthesised derivatives was measured by scavenging activity against DPPH (2,2-Diphenyl-1-picrylhydrazyl) radical and qualitative ABTS (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) free radical scavenging assay and it was found that the compounds showed antioxidant activity. AChE inhibitory activity of the synthesised derivatives was tested against Donepezil for their ability to inhibit acetylcholinesterase (AChE) using a modification of Ellman’s spectrophotometric method. However, no significant inhibitory activity was observed.