Letters in Drug Design & Discovery - Volume 6, Issue 3, 2009

The present paper evaluates the effect of DEγE on the epileptiform EEG activity in a mouse model of epilepsy, i.e., the DBA/2J epileptiform pattern and the DBA/2J audiogenic seizures. Repeated neonatal mild stress, such as manipulation of pups and a brief isolation from the dam performed daily for a few weeks, induces brain, behavioural and hormonal alterations which may perdure up to adult and senescent ages. Since DEγE (a well known β-endorphin fragment) was able to modulate the epileptiform activity in animal models, we started an investigation to verify whether DEγE could modulate epileptiform EEG activity in DBA/2J mice. Litters of DBA/2J mice born in our laboratories were used. Pups of the litter W once per day were separated from mam for ten minutes, weighed and injected with distilled water sc or DEγE (50 and 100 mg/kg), from day 2 to day 21 (weaning). At the age of 60-90 days, mice under general (ketamine-xylazine) plus local (xylocaine) anaesthesia were implanted with 4 stainless electrodes in the anterior and posterior sensorimotor cortex bilaterally. At least 6 days later, they were placed in a sound-proof room, and EEG and motor activity were recorded for 60 min. Two parameters were evaluated: sleep-wakefulness cycle and epileptiform activity. The latter parameter consisted of four different data: spikes, polispikes, series of spike-and-waves, and series of polispike-and-waves. Our results show that a chronic mild stress in neonatal period, as daily injection of distilled water sc., in adult age induced a significant reduction of mean number of series of polispike-and-wave versus control; this effect in mice, chronically treated with DEγE at both doses 50 ng/μL and 100 ng/μL, was also observed. Chronic neonatal mild stress also induced alterations in response to visual evoked potentials. Flash evoked potentials of mice injected with distilled water appeared with a significant delay of latency at the frequency of 1 Hz and at the lower intensity of luminous stimulation versus control; we observed the same trend in chronically treated with DEγE 50 and 100 ng/μL/mice. The results of our experiments indicate that adult mice which had received DEγE showed a consistent reduction in mean number of series of polispike-and-wave versus controls. Other epileptiform parameters in stressed mice did not show consistent alteration, neither sleep-wakefulness cycle did. Also audiogenic seizures did not show consistent differences between groups. We conclude that some, but not all epileptiform parameters in a genetic model of epilepsy in mice are sensitive to DEγE.

Some novel benzoquinones and their dimethoxy chemical precursors were synthesized based on shikonin structural features. The quinone functionality showed strong .OH radical scavenging, whereas benzoquinones with an α- hydroxy-containing saturated side chain exhibited increased soybean lipoxygenase inhibition. Compounds 5, 5b and 7 were superior to indomethacin in vivo in the carrageenin-induced rat paw edema inhibition.

Ten dibenzofurans were synthesized and evaluated as human immunodeficiency virus (HIV)-1 inhibitors in vitro for the first time. Among these compounds, compounds 1, 6, 7 and 8 demonstrated significant anti-HIV-1 activity. Especially compound 1 showed the highest anti-HIV-1 activity with TI value larger than 16.18. Meanwhile, some structureactivity relationships were also observed and will provide a new lead for design and discovery of more potent dibenzofurans as new HIV-1 inhibitors.

Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. In an effort to develop new therapies to treat breast cancer, a series of 1-phenethyl-1H-[1,2,4]triazole derivatives (6a-6h) were synthesized and evaluated for their efficacy as aromatase inhibitors. Biological tests suggest that these compounds exhibit mild to moderate inhibitory activity to aromatase.

Urease is an enzyme responsible for the hydrolysis of urea into ammonia and carbamate. Humans infected by urease are exposed to a risk of chronic gastritis or cancer. Urease inhibitors have attracted a great deal of attention for their potential as new anti-ulcer drugs. Here, we describe the synthesis of series of hydroxamic acid compounds designed as inhibitors of urease.

Quantitative structure-activity relationship analysis of some recently synthesized thiourea derivatives was studied for their cytotoxicity data (CC50) in MT-4 cells. The statistically significant 2D-QSAR model-1 (r2 = 0.964, r2 CV = 0.943 and r2 -pred = 0.961) constructed by genetic function approximation (GFA) methodology was obtained when the number of descriptors was set to 4, indicating that the descriptors of the lowest unoccupied orbital energy (LUMO), radius of gyration (RadOfGyration) and E-state indices (S_ssCH2 and S_aaCH) crucially contributed to biological activity. The validation of the model was done by full cross-validation tests, randomization tests and external test set prediction. Molecular field analysis (MFA) on the corresponding training set investigated the substitutional requirements for the favorable receptor-drug interaction using genetic partial least squares (G/PLS) method, showing that both steric and electrostatic fields play a major role in determining activity. The results derived by combining both methodologies may be useful in further prediction of cytotoxity data (CC50) of corresponding anti-HIV drugs.

A series of new coumarin linked naphthalimides (16a-g; 18a-g) was synthesised and evaluated for their in vitro anticancer activity against six cancer cell lines. Most of the compounds investigated have shown good to moderate anticancer activity against colon, breast and lung cancer cell lines. Thermal denaturation studies indicated that some compounds exhibited DNA binding ability. They were also found to be active against gram-positive and gram-negative bacterial strains as well as a few fungal strains.

Kinetic and crystallographic studies on the formation of the complex between iodoacetate and the enzyme glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi were conducted in order to investigate the mechanistic and structural basis underlying enzyme inactivation. The crystallographic complex reveal important structural features useful for the design of novel inhibitors.

Aerolysin (Aer) is a pore forming toxin that plays important role in pathogenesis of Aeromonas hydrophila which causes hemorrhagic septicemia in aquatic and terrestrial animals including humans. Aerolysin aggregates in the forms of oligomers on the surface of animal RBCs and its ability to bind with Glycosylphosphatidyl inositol (GPI) anchored protein receptor. The primers were designed for Aer gene and amplified to target the complete ORF of Aeromonas hydrophila; later it was sequenced. Homology modeling was used to construct the 3-D structure of Aer using known template (PDB: 1PRE) and the stereochemical quality, torsion angle of 3-D structure was validated. Several drugs were used for virtual screening through molecular docking and four drugs viz. Aralia, Gypsogenin, Saponin and TS-saponin are more potent for inhibition of oligomerization of aer through robust binding affinity between protein-drug interactions. The phylogenetic analysis showed that homology of Aer present in A. hydrophila resembled with other bacteria. The findings could help as a beginning in rationale designing of novel drugs and its analogs.

In this paper we reported the design, synthesis of a series of thiazolidinedione derivates. Their PPARγ activity in vitro was assessed using a reporter gene assay. In this series, it was demonstrated that compound 8f, 8g and 8h with substituted sulfonamino thiourea groups exhibited significant partial agonistic effects on PPARγ.

Organic selenides, such as Se-alkyl-selenocysteine and derivatives, are active in suppressing chemically induced mammary carcinogenesis in rats. Here the quantitative structure-activity relationship (QSAR) study of ten related alkyl-chalcogens was performed to correlate their structural properties with the measured chemotherapeutic activities (ED50). The CS Gaussian 98 program with Hartree-Fock/3-21G (d) basis set was applied for molecular properties computations of the optimized models. Electron Density on chalcogen (ED(X)) expressed the strongest influence on anticancer activity of the examined molecules. Linear regression model of the alkyl-chalcogens, log(ED50) = f (ED(X)), was obtained with R2=0.964 and cross-validation parameter q2 pre=0.950. Synergy between organo-selenides and vitamin E in chemotherapeutic activity led to propose novel organoselenium-α- tocopheryl esters as potent anticancer agents. Anticancer activities (log(ED50)) of the designed alkyl-seleno/α-tocopheryl esters (S-1 to S-4) were evaluated using the developed QSAR/alkyl-chalcogens model and the most potent chemotherapeutic agents (ED50(S-1): 2.60 ppm and ED50(S-4): 2.55 ppm). On the other side, previously created QSAR model for in vitro anticancer activity (IC50) for α-tocopherol derivatives, log(IC50)=f (NCH3, logDpH 5.0, O-charge) with R2=0.940 and q2 pre=0.879, was employed with IC50 evaluation of the proposed alkyl-seleno/α-tocopheryl esters (S-1 to S-4). Calculated antiproliferative activities of the designed compounds, IC50(S-1): 25.65μM and IC50(S-4): 31.36μM, were significantly stronger than activities of other related anticancer agents, IC50: 4-1461 μM.

The aim of this paper was to describe the use of a 2-hydroxypropyl beta-cyclodextrin (2-HPβCD) as a tool to improve the chemical stability of tiagabine hydrochloride (TGB). HPLC method was used to quantify TGB. The correlation coefficient of the linearity (r2) of HPLC method was more than 0.999 whilst the limit of detection and the limit of quantification of TGB were 0.6494 μg ml-1 and 1.765μg ml-1 respectively. The effect of 2-HPβCD on the chemical stability of TGB was compared with α-tocopherol and ascorbic acid, the most recognized antioxidants used to enhance the stability of TGB. The stability was expressed by (% w/w) of the total related substances (TRS) of TGB. When TGB was exposed for 24 h to 50°C, the TRS were 3.264% (SD ±0.077) and 3.125% (SD ±0.053) in the presence of α-tocopherol and ascorbic acid, respectively. The TRS of TGB complexed with 2-HPβCD was 2.142% (SD ±0.045). This study demonstrates that 2-HPβCD exhibits an obvious enhancement of TGB chemical stability with a different mechanism compared with the usual antioxidants.