Medicinal Chemistry - Volume 5, Issue 4, 2009

Because of their high resistance rate to the existing drugs, influenza A viruses have become a threat to human beings. It is known that the replication of influenza A viruses needs a pH-gated proton channel, the so-called M2 channel. Therefore, to develop effective drugs against influenza A, the most logic strategy is to inhibit the M2 channel. Recently, the atomic structure of the M2 channel was determined by NMR spectroscopy (Schnell, J.R. and Chou, J.J., Nature, 2008, 451,591-595). The high-resolution NMR structure has provided a solid basis for structure-based drug design approaches. In this study, a benchmark dataset has been constructed that contains 34 newly-developed adamantane-based M2 inhibitors and covers considerable structural diversities and wide range of bioactivities. Based on these compounds, an in-depth analysis was performed with the newly developed fragment-based quantitative structure-activity relationship (FB-QSAR) algorithm. The results thus obtained provide useful insights for dealing with the drug-resistant problem and designing effective adamantane-based antiflu drugs.

The CC Chemokine Receptor 1 (CCR1) is closely related to various chronic inflammatory diseases like rheumatoid arthritis and multiple sclerosis, and plays a crucial role in transplant rejection. Inhibiting its activity with CCR1 antagonists has been proved to be effective in preventing some diseases. A number of in vivo experiments have been carried out to shed light on the underlying mechanism of the interactions between the CCR1 and its ligands. However, their conclusions are still controversial. In this study, ligand-based computational drug design is applied as a new and effective way to study the structure-activity relationship of CCR1 antagonists. Three-dimensional pharmacophore models were generated for CCR1 antagonists, using both HypoGen and HipHop algorithms in Catalyst software. Two optimal pharmacophore models were defined through careful qualification processes. Both of them have four features: one hydrogen-bond acceptor, one positive ionable and two hydrophobic groups. Additional information was obtained through comparison between the two models. Our results can be valuable tools for the discovery and development of specific, highly potent CCR1 antagonists. For Supplement material, please see the online version of the article. For Supplement material, please see the online version of the article.

The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC50 units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction.

The present study is related with the toxicity of Saxitoxin (STX), a neurotoxic compound, produced by certain dinoflagellates. Its main toxicological activity is observed through the blockage of the sodium channels. It might originate a reduction of the amplitude and speed of conduction of the action potentials by the peripheral and central nerves, as well as weakening of the skeletal muscular contraction. The aim of this study was to analyze the effect of STX on serotonin (5- HT) levels in some discrete rat brain regions after acute intraperitoneal (i.p.) administration of 5 and 10 μg Kg-1 STX body weight. 5-HT levels were analyzed at 30, 60 and 120 min after the administration of 5 μg Kg-1 of STX, and 30 min after administration of 10 μg K-1 of the toxin. Animals were sacrificed by cervical dislocation and the brains were removed and dissected in seven regions. Tissue samples were analyzed by using a chromatographic technique with electrochemical detection (HPLC/ED). Our results suggest that systemic administration of the STX reaches the brain producing alterations in neurotransmission increasing the levels of 5-HT in all the brain regions studied. With respect to the serotonin metabolite, 5-hidroxiindoleacetic acid (5-HIAA), we observed an increase in its levels in all the brain regions studied with the high dose of toxin, whereas different alterations were observed with the low dose of toxin.

4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ethyl (6), two potential yaminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t1/2 = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2 H-I,3-benzoxazine ring underwent enzymatic hydrolysis (t1/2 =5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation lime (3 h). Both compounds were tested for their central nervous system activity by using both anticonvulsive and behavioral tests. The anticonvulsive study was performed using the convulsive agent pentetrazole (PTX) and bicuculline. The anticonvulsive study indicated that compound both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.), injected 60 min before PTX (75 mg/kg, i.p.) or bicuculline (10 μg/intracerebroventricular (i.c.v.)/mouse) induced a dose-dependent and significant reduction of the convulsive activity of PTZ and bicuculline whereas it was ineffective if injected immediately before the convulsive agent. Both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.) did not significantly modify animal behavior or the nociceptive threshold of the animals. However, in PTZ- and bicuculline- treated mice, compound 7 showed significant activity, compared to compound 6, because it was active at relatively low doses. The behavior elements considered were locomotor activity, motor coordination, catalepsy, behavior and antinociception. The results of the behavoral study indicate that these new GABA mimetic drugs did not modify the animal behavior. Our data indicate that these new GABA mimetic drug possesses good anticonvulsive activity without altering the animalbehavior and their ability to block bicuculline-induced convulsions suggests that they could be a GABAA mimetic drug. Furthermore, since these compounds are able to act after systemic administration, our data suggest that these new GABA mimetic drug cross the blood-brain barrier.

Quantitative structure activity relationship approach using stepwise regression analysis was applied to a series of 4-quinolone derivatives as high-affinity ligands at the benzodiazepine site of brain GABAA receptors. For the purpose 25 compounds were used to develop models. Statistically significant equations were obtained with high squared correlation coefficient (r2=0.8761, 0.9295 and 0.8705) and low root mean square error (RMSE=0.4844, 0.3894 and 0.4952). The robustness of the model was confirmed with the help of leave one out cross validation method which exhibited high r2 cv values (r2 cv=0.7875, 0.8263 and 0.7927). A good correlation of various molecular shape parameters, like ovality, Szeged index, and energy of the molecule with the GABAA affinity was achieved.

The original quantitative structure-activity relationship (QSAR) formulation was proposed by Hansch and Fujita in the 1960's and, since then QSAR analysis has evolved as a mature science, due mainly to the advances that occurred in the past two decades in the fields of molecular modeling, data analysis algorithms, chemoinformatics, and the application of graph theory in chemistry. Moreover, it is also worthy of note the exponential progress that have occurred in software and hardware development. In this context, a myriad of QSAR methods exist; from the considered “classical” approaches (known as two-dimensional (2D) QSAR), to three-dimensional (3D) and multidimensional (nD) QSAR ones. A distinct QSAR approach has been recently proposed, the receptor-dependent-QSAR, where explicit information regarding the receptor structure (usually a protein) is extensively used during modeling process. Indeed, a limited, but growing number of receptor-dependent QSAR methods are reported in the literature. With no intention to be comprehensive, an overview of receptor-dependent QSAR methods will be discussed along with an in-depth examination of their applications in drug design, virtual screen, and ADMET modeling in silico.

Sesamol has been shown earlier to exhibit antimutagenic (reactive oxygen mediated) and antiageing activity in our lab and it has also been found to exert chemopreventive effect. Here we report the in vitro antioxidant activity of sesamol. As most of the antioxidants act due to their property to auto-oxidise and the pro- or antioxidant activity would depend on the concentration of the agent used and the free radical source, at least 6 dilutions in concentration range of 5- 1000 nmoles of sesamol were selected for each test system. Further the antioxidant activity was compared with a water soluble antioxidant (ascorbic acid). Eventhough some preliminary studies on the antioxidant activity of sesamol have been reported in DPPH assay & inhibition of lipid peroxidation, it is not complete. We, here in report comprehensively (both in terms of the no. of doses and also a variety of test systems being employed) on the antioxidant activity of sesamol. Furthermore, since all the data has been generated by the same workers and under same laboratory conditions, hence is scientifically significant. Also the process of dose selection as discussed earlier is more scientific; and the data treatment, i.e. calculation of IC50 values and comparisons with ascorbic acid has been statistically validated. In conclusion, sesamol was found to be an efficient scavenger of the entire range of ROS in several test systems pointing towards the potential of sesamol to be developed as a possible therapeutic.

This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R, cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780cisR. Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780cisR, and A2780 and A2780ZD0473R are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780cisR cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.

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Triiodobenzoic acid (TIBA) represents the core structure of most clinically used contrast agents for computed tomography and other X-ray procedures. To construct an intracellular radiopaque contrast agent, TIBA was coupled to various different positively and negatively charged fluorescein iothiocyanate (FITC)-labelled peptides. TIBA coupled to the SV40 T Antigen nuclear localization sequence (NLS) stained 80% of human glioma cells and caused cell death. This occurred with C- or N-terminal binding of TIBA and with the correct or mutant NLS. No cell death and only small numbers of stained cells (below 3 %) were observed after incubation with NLS conjugates lacking TIBA or after incubation with TIBA-conjugates containing a negatively charged polyglutamic acid stretch. TIBA-conjugates containing the Antennapedia-derived cell-penetrating peptide penetratin were only nuclearly taken up when TIBA and FITC were coupled to lysines outside the 16-amino acid peptide sequence. The study shows that intracellular TIBA may have potential as a chemotherapeutic agent rather than a contrast agent.

A series of thirteen new megazol derivatives, designed exploring the molecular hybridization approach between megazol (3) and heterocombretastatins (2), was synthesized. These new compounds were tested for in vitro antiparasitic activity upon axenic amastigotes of Leishmania donovani. Biological results led us to identify a new potent megazol derivative (4g), which presents an IC50 = 0.081μg/mL, more active tham the reference drug miltefosine (IC50 = 0.131μg/mL).