Letters in Drug Design & Discovery - Volume 7, Issue 1, 2010

Alzheimer's disease (AD) is one of the most discussed diseases of present time. Because of the aging of our population it is high threat for future. Due to this, new drugs combating AD are still developed. In this study, twelve bisquaternary isoquinolinium derivatives differing in the linker between two heteroarenium rings were synthesized and tested for their potency to inhibit brain cholinesterases. According to the obtained in vitro results, the anticholinesterase activity grew up with the length of the connection chain. Possible binding to the enzyme cavity was described using software Autodock. Moreover, LogP and molecular volume of prepared compounds were predicted. As resulted, the highest probability of synthesized compounds to penetrate blood-brain barrier could be expected for the compound with linker having eight methylenes.

The docking study on a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives with acetylcholinesterase has been demonstrated. The synthesis and characterization of a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were described. All target compounds were evaluated in vitro for the inhibitory activities against AChE via Ellman colorimetric assay. Most of the target compounds possessed anti-acetylcholinesterase activity. The preliminary structure-activity relationships were discussed.

GABA was synthesized by deethoxycarbonylation, ester hydrolysis and nitrile reduction of a highly functionalized intermediate obtained by alkylation of diethyl cyanomalonate with ethyl bromoacetate. By judicious employment of D2O or NaBD4 in one of the three functional group transformation steps, deuterium was selectively introduced into each of the three possible sites in GABA.

The synthesized compounds 1-7 were evaluated for their antidepressant activity, among which 2-phenylethyl alcohol 1 and isoamyl phenylacetate 3 showed 43 % and 37 % reduction in immobility time in mice using forced swim test, thereby, displaying antidepressant- like activity. Compound 1 and 3 were equipotent and both these compounds were 2x effective than the standard drug phenelzine. Considering other esters it appears that a decrease in alkyl chain length or addition of either NO2 or OH groups to the phenyl ring caused a marked decline in the antidepressant-like activity.

A series of nitric oxide-donating derivatives of [1,2,4]triazol-5(4H)-one (9a-f and 15a-f) as a novel class of angiotensin II receptor AT1 antagonists have been designed and synthesized by coupling furoxan and nitric oxide with lead compound 1. The synthesized compounds were evaluated for their antagonism of AT1 receptor with induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9b, 15b and 15d exhibited potent antagonistic activity of AT1 receptor. Moreover 9b, 15b, 15d, 15e had good maximum NO release amount of this series.

The subject of this work was an inhibition of cellular prion expression in vitro and in vivo by antisense oligodeoxyribonucleotides, incorporated into cationic immunoliposomes. It was shown that asODNs are able to reduce the level of PrPc expression in vitro and in vivo.

Some novel pyrazole acyclonucleosides were prepared through binding of pyrazole-3,5-substituted derivatives with acyclic substituents mimetizing individual fragments of the ribose ring such as: 1-[(2-hydroxyethoxy) methyl], 1-[4-(hydroxybutyl)], 1-[3- (hydroxypropyl)] and 1-[(2-hydroxyethyl amino) methyl]. Their syntheses were performed from easily accessible starting materials. The prepared compounds were evaluated for their antibacterial activity. Structure-activity relationship studies (SAR) indicate that introduction of modified arm in N1 position of pyrazole moieties has not any impact on the biolgical activity.

This investigation reports on the drug interactions between chitosans and antibiotics in Staphylococcus aureus. The combination study shows that chitosan oligosaccharides have synergistic effect in combination with tetracycline, ceftriazone and sulfamethoxazole. Also, high molecular weight chitosan was found to be effective against Staphylococcus aureus in combination with Sulfamethoxawzole. These results indicate the potential efficacy of chitosans in combinations with antibiotics for enhancing total biological activity.

Disintegrins are natural toxins found in snake venom having anti angiogenic activity. The KTS disintegrins group appears to be the most interesting as specific blocking agent of tumor growth. We report the chemical synthesis of three KTS disintegrins (Lebestatin, Obtustatin and Viperistatin) carried out with different substitution. The activity of these synthetic peptides (41 aa) and native Lebestatin purified from venom was compared with cell adhesion and migration assays. Synthetic and native Lebestatin inhibit cell adhesion of PC12 cells at 0.2 nM and integrin-dependent migration of CHO cells at 1 nM. This study shows that Lebestatin has the highest activity followed by Obtustatin and then Viperistatin in the two assays. Circular dichroism spectra of these KTS disintegrins show that their folding is similar. Molecular modeling shows that two arginines (8 and 24) and two lysines (21 and 32) have probably their chemical function interacting with integrins in protruding from the surface of Lebestatin. This study should help to design a lead compound to discover a new family of anti-angiogenic drugs.

Six new N,N-bis(1,2,4-triazol-1-ylmethyl)amines have been prepared in one step by condensation of 1- (hydroxymethyl)triazole with a series of amines. These reactions were carried out in refluxed CH3CN for 4 hours. The products were recuperated with excellent and good yields (75-89.5%). Compounds (3a-f) were screened for their antifungal activity against the budding yeast Saccharomyces cerevisiae and their antibacterial activity against Escherichia coli.

Despite the advances in medicine and the emergence of new antifungal agents, fungal infections remain a significant cause of morbidity and mortality. Azoles are widely used as antifungal agents. Azoles interfere with the conversion of lanosterol to ergosterol by inhibiting a fungal cytochrome P450enzyme, lanosterol 14α-demethylase. Resistance to azoles, particularly fluconazole, is emerging to Candida albicans, after long-term suppressive therapy. Thus, there is an urgent need for newer potent antifungals to combat resistance developed against widely used azoles. In present work, we report synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various concentrations to obtain minimum inhibitory concentration (MIC).

The molecular details of the clinical side effects of nonsteroidal anti-inflammatory drugs are poorly understood. In order to better understand the molecular basis of these effects, the interactions of Ibuprofen, Naproxen and Diclofenac with dimyristoylphosphatidylethanolamine (DMPE) phospholipid bilayers as model for a cell membrane were performed. By applying FTIR, data for the headgroup vibrations give no indication for an essential contribution of this molecular part, in particular the phosphate bands, in the interaction with the NSAID. In contrast, the evaluation of lipid vibrational bands of DMPE indicates a considerable fluidization of its hydrocarbon chains, being strongest for Diclofenac. Summarizimg the data also from ITC and DSC experiments, it can be stated that the interaction is essentially entropy driven.

Human E1 is a key player in protein ubiquitination, however the E1 structure is not available. In this paper, we describe the derivation of a human E1 structure using molecular modelling based on the crystal structure of S. cerevisiae E1 and M. Musculus E1. Key interactions between our E1 model and ubiquitin are also discussed.

Glycerol monostearate was used as a pellet-aid to prepare tiagabine HCl/2-HPβCD inclusion complex pellets (an antiepileptic agent partially included into the 2-HPβCD cavity to improve its stability). The pellitization of tiagabine HCl/2-HPβCD inclusion complex (1:1 stoichiometric composition) using 27.3% of melted GMS (60°C) in its liquid form as wetting agent, 30% of microcrystalline cellulose (pellet-forming agent) and 3% of kollidone-30 (binder) was studied. Pellitization was prepared using extrusion/spheronization method. >b 80% of pellets, size ranging between 800-1000μm, were obtained indicating a significant pellet yield. The disintegration test of the pellets complied with the Eur. Ph. Limit (0.8%). The TGB pellets formed were better sized and spherically shaped than when GMS was used in its liquid form. Pellets obtained using tiagabine HCl/2-HPβCD inclusion complex after addition of GMS with very little water content (< 5%) have also a spherical shape, retain their integrity in dissolution medium, which suggested that coatings will not burst prematurely due to granule swelling and release their TGB load rapidly 65-85% in 15min in a phosphate buffered dissolution medium.