CH functionalization has recently attracted considerable attention in organic synthesis. Although it provides the same products as already well established cross-coupling methodologies, it has the advantage of avoiding the use of metallic species such as Grignard, boron, silicon, and tin compounds. Thus, regarding both atom and step economy, the formation of carbon–carbon bonds through CH functionalization is a convenient methodology with broad application in total synthesis and medicinal chemistry.

Phenanthridinones are key core units found in many natural products which exhibit interesting biological and pharmaceutical properties. In the last years, novel alternative synthetic approaches have been developed to the synthesis of the phenanthridinone core and related lactams. The palladium-catalyzed intramolecular direct CH arylation reaction has proved to be one of the most efficient method for the access to such valuable compounds. However, relative big amounts of catalysts are usually required. Herein, we report an unprecedented palladium-catalyzed intramolecular direct arylation for the general access of phenanthridinones under very low catalyst loadings. With only 0.05 mol%, a palladium NCP pincer complex promotes efficiently the direct functionalization of a series of N-arylbenzanilides and N-arylsulfonamides which constitutes an effective, versatil and environmentally attractive procedure for the preparation of phenanthridinones, biaryl sultams and related heterocyclic derivatives.

The oxidation of benzylic alcohols is a ubiquitous transformation in organic chemistry due to the relevance of aryl ketones, present in natural products and pharmaceutically active compounds and also intermediates in the synthesis of agrochemicals, medicines and other functional materials. Numerous oxidizing agents are available to effect this key reaction. In most instances, these reagents are required in stoichiometric amounts and are usually toxic, or hazardous, or both. In this context, considering environmental and safety issues, oxygen would be the reagent of choice for such organic transformation. Although much effort has been devoted to aerobic oxidation of benzyl alcohols, the amounts of metal catalyst are still relatively high ( 0.1-10 mol % ) and, sometimes, oxygen pressures above 5 atms.

In this context, we have discovered that systems based upon 1,2,4-triazole ligands and simple Ni (II) salts show extremely high catalytic activity in the aerobic oxidations of alcohols. In fact, primary and secondary benzylic alcohols have provided the corresponding carboxylic acid derivatives by using molecular oxygen at atmospheric pressure, in the presence of a combination of nickel(II) bromide and 1,2,4-triazole or, alternatively, a 1,2,4-triazole pincer ligand at such a low catalytic loading as 10^-5 mol%. This catalytic system has proven to be efficient also for the benzylic C-H oxidation.

Nitric oxide (NO) is involved in acute μ-opioid receptor (MOR) desensitization in the locus coeruleus (LC) and in the neuroadaptations following chronic morphine administration. However, the role of NO and NO-derived reactive oxygen species (ROS) in the development of cellular tolerance to different opioids remains unclear. Herein, we examined the effect of the selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 30 mg/kg/12 h, i.p.) and the antioxidants Trolox + ascorbic acid (TX+AA; 40 and 100 mg/kg/day, respectively, i.p.) and U-74389G (10 mg/kg/day, i.p.) on the development of cellular tolerance induced by morphine, methadone and fentanyl. For induction of morphine tolerance, rats were treated subcutaneously with a slow release emulsion containing free base morphine (200 mg/kg, 3 days). For methadone (60 mg/kg/day, 6 days) and fentanyl (0.2 mg/kg/day, 7 days), tolerance was induced by s.c. implantation of osmotic pumps. Concentration-effect curves for the inhibitory effect of Met⁵-enkephalin (ME; 0.05-12.8 μM, 2x, 1 min) on the firing rate were performed by single-unit extracellular recordings of LC neurons from rat brain slices. Morphine, methadone and fentanyl treatments shifted to the right concentration-effect curves for ME and increased the EC₅₀ by 2-4 folds. Co-administration of TX+AA or U-74389G in morphine-treated animals prevented the development of tolerance in LC neurons. Conversely, co-treatments with U-74389G or 7-NI failed to affect the induction of cellular tolerance after methadone or fentanyl treatments. Our results suggest that MOR agonists with different intrinsic efficacies cause variable degrees of cellular tolerance in LC cells. Moreover, NO/ROS pathways are differentially involved in opioid tolerance after prolonged treatments with morphine, methadone and fentanyl.

The natural tendency of proteins to bind to each other, as well as to many different molecules, forming stable and specific complexes is fundamental to all biological processes. The structural and functional description of protein-protein and protein-ligand complexes and their comprehension is a key concept, not only to increase the scientific knowledge in basic terms but also for the application to the biomedical and pharmaceutical industry. In this work we have look for more accurate ways of predicting the crucial residues for complex binding (Hot-spots) that can be used to model protein structure, dynamics and function. We developed an algorithm based in innovative series of descriptors, which have not been used in hot-spot determination and that can be applied to both protein-protein and protein-nucleic acid interfaces HS detection. A web-server for public use of the new methodological approaches was built and can be accessed at  http://bio-aims.udc.es/MolStructPred.php

Prostanoids are known to regulate several physiological functions and to play an important role in certain pathophysiological situations such as inflammation. Prostaglandin E₂ receptors (EP) are members of the G protein-coupled receptor superfamily. Four subtypes have been described: EP2 and EP4 (coupled to G_s proteins) and EP1 and EP3 (coupled to G_i/o proteins). To date, the function of the prostanoid system in the brain has not been well characterized. The locus coeruleus (LC), the main noradrenergic nucleus in the brain, has been described to express the EP3 receptor. The aim of this study was to characterize the functional relevance of EP3 receptors in the LC by single-unit extracellular recordings in rat brain slices. We performed concentration-effect curves for different endogenous derivatives and selective agonists of EP3 receptors. Thus, increasing concentrations of the EP3/EP1 agonist sulprostone (0.3-80 nM) fully inhibited the neuronal activity of LC cells, with an EC₅₀ value of 15 nM (n = 9). The EP3 receptor antagonist L-798,106 (10 µM) caused a rightward shift (> 8 fold) in the concentration effect curve for sulprostone, but the EP2 receptor antagonist PF04418948 (10 µM) or the EP4 receptor antagonist L-161,982 (10 µM) failed to cause any rightward shift of sulprostone effect. On the other hand, perfusion with the endogenous PGE₂ (0.3 nM-1.28 µM) or the PGE₁ analogous misoprostol (0.3-320 nM) induced a concentration-dependent inhibition of the firing rate of LC cells, with EC₅₀ values being 51 nM and 112 nM respectively. Likewise, only the EP3 antagonist L-798,106 (10 µM) caused a rightward shift (> 8 fold) in the concentration-effect curves for these prostanoid agonists (n = 5). In conclusion, LC neurons are regulated in an inhibitory manner by the prostanoid system likely through the EP3 receptor.

ABSTRACT:

 Fuzzy logic first established in July,1964 by Lofti A.  Zadeh, is usually used to develop cost-effective approximate solutions to complex real-world problems exploiting the tolerance of imprecision.

The present study attempts to develop a general computational technique based on fuzzy multi-dimensional membership function using forward selection rule for discriminating two different situations which is basically non-linear. Incidentally the technique suggested here is validated with atmospheric data.

Earlier the fundamental principal component analysis (PCA) technique was applied to identify the significant parameters for the occurrence of pre-monsoon thunderstorms (TS) in Kolkata. They showed how the linear discriminant analysis (LDA) technique alone as well as in conjunction with PCA can be successfully applied for the purpose (Ghosh et al. 1999, 2004; Chatterjee et al., 2009). Also a comparative study was performed between the existing multivariate technique, the linear discriminant analysis and a technique based on fuzzy membership roster method (Chatterjee et al., 2011). Recently a fuzzy –neuro based algorithm for weather prediction has been developed (T. Rahman et al. 2014).

 The main objective of the study is to address the numerical imprecision of some quantified physical variables. In this rule, a product form is taken to construct the multivariate membership function where the univariate membership function is Gaussian in nature as well as continuously differentiable. Since the parameters may have different units so they are made dimensionless before taking the product. To develop the technique no software package or fuzzy toolbox is used. The program for the study is developed by the authors themselves.  

This rule is applied to two datasets of different categories consisting of the parameters of the days with convective development and fair weather respectively during pre-monsoon season of Kolkata (22.53ºN, 88.33ºE), India. Basic parameters for discriminating the situation (convective development and fair weather in pre-monsoon season of Kolkata) is constructed from the known data set of 12 years covering the period 1985-1996. The results are validated for the period 1997-1999 using the dataset consisting of variables of unknown nature. The study reveals that the technique can classify the two different situation to give the best possible combination of parameters with atmost 88% success rate. Moreover, the study indicates that the two datasets are structurally different.

The technique suggested here is expected to work in any other domain too. It is found that the method works with better accuracy than the existing ones so far the atmospheric parameters are concerned. The detail will be discussed in the literature.

The interest of coumarins as antioxidant agents has attracted much attention in recent years. A quantitative structure-activity relationship (QSAR) study of the DPPH• (2,2-diphenyl-l-picrylhydrazyl) radical scavenging ability of chemical compounds, based on the 0-3D DRAGON molecular descriptors and an artificial neural networks (ANN) technique was developed. The built mathematical model showed a correlation coefficient for the training set (R²) = 0.71, an external correlation coefficient ( and it was used to predict the antioxidant activity of 4-hydroxycoumarin derivatives. Besides, an experimental in vitro assay was developed for the reference compound of this group (4-hydroxycoumarin) and the results obtained confirmed the predictions made by the ANN.

Friedel-Crafts alkylation is one of the most important methods used in organic chemistry to create carbon-carbon bonds. The traditional conditions using alkyl halides activated by a Lewis or Brønsted acid has been widely described in the literature. Nevertheless, the Friedel-Crafts reaction using aldehydes or ketones as substrates, known as hydroxyalkylation, has been poorly described.

The development of regioselective Friedel-Crafts conditions is a challenge in organic synthesis. The growing interest in developing a “metal and solvent free" reactions justifies the particular attention that the Brønsted acids have received as an alternative to toxic and precious metals.

These last years the triarylmethanes attract considerable attention due to their applications in fine, medicinal and industrial chemistry. They have been used as protecting groups, dyes and or photochromic agents. They also showed interesting biological properties including anti-tumor and antioxidant activities. Different methods of preparation of symmetrical triarylmethanes have been described in the literature, nonetheless the synthesis of unsymmetrical ones has been very little explored.

In this work we describe an efficient regioselective method to prepare unsymmetrical triarylmethanes from enriched aromatic compounds, via a Friedel-Crafts hydroxyalkylation catalyzed by Brønsted acids using pyridylarylcarbinols as alkylating agents. The method described here is consistent with the principles of green chemistry and has significant advantages, such as the use of an inexpensive catalyst and the mild conditions. The method described is regioselective, offers a good yields, shorter reaction times and a possible extension to various substrates.

Drug resistance is a serious issue that compromises the efficacy of many drugs and antibiotics.  One mechanism underlying the development of resistance is the alternation in the target enzyme or receptor resulting in gradual silencing of the target to the effects of the ligands.  Basak et al developed a method called differential QSAR (DiffQSAR) whereby test data of drugs on their effects on the sensitive and resistant targets are used to characterize the phenomenon of drug resistance using mathematical molecular descriptors.  This paper will summarize our research in this area.

Surfactin A, a cyclic lipopeptide from Bacillus subtilis, exhibited a wide spectrum therapeutic profile. But it’s drug likeness has not been thoroughly assessed yet. Thus, the objective of the present work was to simulate it’s drug likeness by predicting the pharmacokinetic and toxicological profiling parameters. ADME profiling was carried out by using StarDrop. Integrated Derek Nexus with StarDrop was used for the toxicological prediction against 40 toxicological end points. Metabolism of Surfactin A was modelled with three isoforms of cytochrome P450: 3A4, 2D6 and 2C9; and composite site lability (CSL) was analyzed. Only the alkyl regions in Surfactin A were found to be moderately labile to metabolism, indicating their tendency to get oxidized and form dealkylated Surfactin A. Toxicological prediction suggested that Surfactin A is not carcinogenic, mutagenic, teratogenic, hepatotoxic, neurotoxic, nephrotoxic and even clean for rest of the toxicological end points. Good human intestinal absorption (HIA) and poor blood brain barrier (BBB) crossing ability were also predicted for Surfactin A.