Pharmacological Interest Research Articles

Pharmacognostic, Phytochemical and Pharmacological Review of Ficus religiosa

Ficus Religiosa is a perennial evergreen tree. It is belonging to moraceae own circle of relatives and In India its commonly referred to as Peepal tree, Bodhi tree. The tree is local of India. Peepal tree incorporates many main bioactive components which own diverse pharmacological interest and additionally beneficial with inside the remedy of diverse illnesses and problems consists of Diabetes, ulcer, cancer, epilepsy, pores and skin illnesses, flu and additionally own many medicinal interest together with anti-inflammatory interest, analgesic interest, anti-acetyl cholinesterase interest, anti-helminthic interest and wound recovery interest and additionally famous a few different interest together with antibacterial, anti-fungal etc. All components of tree (leaves, bark, fruit, root and flower) are beneficial for the preparation of many ayurvedic components and beneficial for making natural treatments etc. that is beneficial for deal with and cure diverse illnesses. The tree product now no longer reasons any main or intense aspect effect. The foremost intention of this review/take a look at turned into to find out or sell the information approximately this multipurpose medicinal valued tree.

Pharmacological inhibitors of β-cell dysfunction and death as therapeutics for diabetes.

More than 500 million adults suffer from diabetes worldwide, and this number is constantly increasing. Diabetes causes 5 million deaths per year and huge healthcare costs per year. β-cell death is the major cause of type 1 diabetes. β-cell secretory dysfunction plays a key role in the development of type 2 diabetes. A loss of β-cell mass due to apoptotic death has also been proposed as critical for the pathogenesis of type 2 diabetes. Death of β-cells is caused by multiple factors including pro-inflammatory cytokines, chronic hyperglycemia (glucotoxicity), certain fatty acids at high concentrations (lipotoxicity), reactive oxygen species, endoplasmic reticulum stress, and islet amyloid deposits. Unfortunately, none of the currently available antidiabetic drugs favor the maintenance of endogenous β-cell functional mass, indicating an unmet medical need. Here, we comprehensively review over the last ten years the investigation and identification of molecules of pharmacological interest for protecting β-cells against dysfunction and apoptotic death which could pave the way for the development of innovative therapies for diabetes.

Vilsmeier-Haack Cyclisation as a Facile Synthetic Route to Thieno [2,3- b] Quinolines (Part I)

Abstract: Quinoline ring system is extensively dispensed in natural products, especially in alkaloids. Moreover, thieno[2,3-b]quinolines have vast biological activities, including urea transporter inhibition, anti-microbial, antitumor, antioxidant, anti-inflammatory, and antiproliferative EGFR tyrosine kinase inhibition. Vilsmeier-Haack is considered the most facile and promising set of synthetic routes, leading to 2-chloro-3-formylquinolines through Vilsmeier-Haack cyclisation of N- arylacetamides, which are subsequently used as key intermediates for the synthesis of thieno[2,3-b]quinolones (Tqs). Many varieties of thieno[2,3-b]quinolines (Tqs) ring systems, specifically concerning medicinal chemistry, have been developed over the past decade. In light of these facts, this review presents a systematic and comprehensive survey of the method of preparation and the chemical reactivity of thieno[2,3-b]quinolines through the Vilsmeier-Haack reaction. In this study, the methods of preparation and the chemical reactivity of (Tqs) by using the Vilsmeier-Haack reaction are discussed. Since the beginning of the 21st century, they have been advancing towards synthesizing substituted Tqs. It can be concluded that substituted Tqs can be used as building blocks for the synthesis of polyfunctionalized heterocyclic compounds with pharmacological interest.

The crucial role of adhesion in the transmigration of active droplets through interstitial orifices

Active fluid droplets are a class of soft materials exhibiting autonomous motion sustained by an energy supply. Such systems have been shown to capture motility regimes typical of biological cells and are ideal candidates as building-block for the fabrication of soft biomimetic materials of interest in pharmacology, tissue engineering and lab on chip devices. While their behavior is well established in unconstrained environments, much less is known about their dynamics under strong confinement. Here, we numerically study the physics of a droplet of active polar fluid migrating within a microchannel hosting a constriction with adhesive properties, and report evidence of a striking variety of dynamic regimes and morphological features, whose properties crucially depend upon droplet speed and elasticity, degree of confinement within the constriction and adhesiveness to the pore. Our results suggest that non-uniform adhesion forces are instrumental in enabling the crossing through narrow orifices, in contrast to larger gaps where a careful balance between speed and elasticity is sufficient to guarantee the transition. These observations may be useful for improving the design of artificial micro-swimmers, of interest in material science and pharmaceutics, and potentially for cell sorting in microfluidic devices.

Mediterranean Lavenders from Section Stoechas: An Undervalued Source of Secondary Metabolites with Pharmacological Potential.

Globally, climate change and wildfires are disrupting natural ecosystems, thus setting several endemic species at risk. The genus Lavandula is widely present in the Mediterranean region and its species, namely, those included in the section Stoechas, are valuable resources of active compounds with several biological assets. Since ancient times lavenders have been used in traditional medicine and for domestic purposes. These species are melliferous, decorative, and essential oil-producing plants with a high economic interest in the pharmaceutical, flavor, fragrance, and food industries. The essential oils of Lavandula section Stoechas are characterized by high amounts of 1,8-cineole, camphor, fenchone, and specifically for L. stoechas subsp. luisieri one of the major compounds is trans-α-necrodyl acetate. On the other hand, the diversity of non-volatile components like phenolic compounds, such as phenolic acids and flavonoids, make these species an important source of phytochemicals with pharmacological interest. Rosmarinic, caffeic, and salvianolic B acids are the major phenolic acids, and luteolin and eriodictyol-O-glucuronide are the main reported flavonoids. However, the concentration of these secondary metabolites is strongly affected by the plant's phenological phase and varies in Lavandula sp. from different areas of origin. Indeed, lavender extracts have shown promising antioxidant, antimicrobial, anti-inflammatory, and anticancer properties as well as several other beneficial actions with potential for commercial applications. Despite several studies on the bioactive potential of lavenders from the section Stoechas, a systematized and updated review of their chemical profile is lacking. Therefore, we carried out the present review that gathers relevant information on the different types of secondary metabolites found in these species as well as their bioactive potential.

Possible new routes to 3′-thionucleotides and their polymers of pharmacological and prebiotic interest

Possible new routes to 3′-thionucleotides and their polymers of pharmacological and prebiotic interest

Therapeutic Potential of Phytocannabinoid Cannabigerol for Multiple Sclerosis: Modulation of Microglial Activation In Vitro and In Vivo.

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently receiving much attention. Cannabigerol is a main phytocannabinoid, which has attracted significant pharmacological interest due to its non-psychotropic nature. In this research, we studied the effects of cannabigerol on microglial inflammation in vitro, followed by an in vivo study. Cannabigerol attenuated the microglial production of nitric oxide in BV2 microglia and primary glial cells; concomitant treatment of the cells with cannabigerol and telmisartan (a neuroprotective angiotensin receptor blocker) decreased nitric oxide production additively. Inducible nitric oxide synthase (iNOS) expression was also reduced by cannabigerol. Moreover, tumor necrosis factor-α (TNF-α), a major cytokine involved in MS, was significantly reduced by cannabigerol in both cell cultures. Next, we studied the effects of cannabigerol in vivo using a mice model of MS, experimental autoimmune encephalomyelitis (EAE). The clinical scores of EAE mice were attenuated upon cannabigerol treatment; additionally, lumbar sections of EAE mice showed enhanced neuronal loss (relative to control mice), which was restored by cannabigerol treatment. Altogether, the set of experiments presented in this work indicates that cannabigerol possesses an appealing therapeutic potential for the treatment of MS.

GPCR in Adipose Tissue Function-Focus on Lipolysis.

Adipose tissue can be divided anatomically, histologically, and functionally into two major entities white and brown adipose tissues (WAT and BAT, respectively). WAT is the primary energy depot, storing most of the bioavailable triacylglycerol molecules of the body, whereas BAT is designed for dissipating energy in the form of heat, a process also known as non-shivering thermogenesis as a defense against a cold environment. Importantly, BAT-dependent energy dissipation directly correlates with cardiometabolic health and has been postulated as an intriguing target for anti-obesity therapies. In general, adipose tissue (AT) lipid content is defined by lipid uptake and lipogenesis on one side, and, on the other side, it is defined by the breakdown of lipids and the release of fatty acids by lipolysis. The equilibrium between lipogenesis and lipolysis is important for adipocyte and general metabolic homeostasis. Overloading adipocytes with lipids causes cell stress, leading to the recruitment of immune cells and adipose tissue inflammation, which can affect the whole organism (metaflammation). The most important consequence of energy and lipid overload is obesity and associated pathophysiologies, including insulin resistance, type 2 diabetes, and cardiovascular disease. The fate of lipolysis products (fatty acids and glycerol) largely differs between AT: WAT releases fatty acids into the blood to deliver energy to other tissues (e.g., muscle). Activation of BAT, instead, liberates fatty acids that are used within brown adipocyte mitochondria for thermogenesis. The enzymes involved in lipolysis are tightly regulated by the second messenger cyclic adenosine monophosphate (cAMP), which is activated or inhibited by G protein-coupled receptors (GPCRs) that interact with heterotrimeric G proteins (G proteins). Thus, GPCRs are the upstream regulators of the equilibrium between lipogenesis and lipolysis. Moreover, GPCRs are of special pharmacological interest because about one third of the approved drugs target GPCRs. Here, we will discuss the effects of some of most studied as well as "novel" GPCRs and their ligands. We will review different facets of in vitro, ex vivo, and in vivo studies, obtained with both pharmacological and genetic approaches. Finally, we will report some possible therapeutic strategies to treat obesity employing GPCRs as primary target.

Rapid One-Step Capturing of Native, Cell-Free Synthesized and Membrane-Embedded GLP-1R.

G protein-coupled receptors (GPCRs) are of outstanding pharmacological interest as they are abundant in cell membranes where they perform diverse functions that are closely related to the vitality of cells. The analysis of GPCRs in natural membranes is laborious, as established methods are almost exclusively cell culture-based and only a few methods for immobilization in a natural membrane outside the cell are known. Within this study, we present a one-step, fast and robust immobilization strategy of the GPCR glucagon-like peptide 1 receptor (GLP-1R). GLP-1R was synthesized in eukaryotic lysates harboring endogenous endoplasmic reticulum-derived microsomes enabling the embedment of GLP-1R in a natural membrane. Interestingly, we found that these microsomes spontaneously adsorbed to magnetic Neutravidin beads thus providing immobilized membrane protein preparations which required no additional manipulation of the target receptor or its supporting membrane. The accessibility of the extracellular domain of membrane-embedded and bead-immobilized GLP-1R was demonstrated by bead-based enzyme-linked immunosorbent assay (ELISA) using GLP-1R-specific monoclonal antibodies. In addition, ligand binding of immobilized GLP-1R was verified in a radioligand binding assay. In summary, we present an easy and straightforward synthesis and immobilization methodology of an active GPCR which can be beneficial for studying membrane proteins in general.

Chemistry of 2-(Pipridin-1-yl) and/ or 2-(Morpholin-1-yl) Quinolines (Part II): Synthesis, Reactivity and Biological Activities

Background: Vilsmeier-Haack formylation of N-arylacetamides and used them as a key intermediate for preparation of 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinoline-3- carbaldehydes. these used as precursors for the synthesis of 2-(piperidin-1-yl) and/ or 2-(morpholin- 1-yl) quinoline derivatives through the reaction with active methyl and/ or methylene component, Claisen-Schmidt condensation, one-pot multicomponent reactions (MCRs), reductive amination, Grignard reaction, etc. Methods: This review demonstrates the synthesis of 2-chloroquinoline-3-carbaldehyde derivatives, through Vilsmeier-Haack formylation of N-arylacetamides that used as a precursor for preparation of 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinoline- 3-carbaldehydes and reacted them with various reagents to form the 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinolines derivatives. Results: Many 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinolines derivatives were achived through the reaction with active methyl and/ or methylene component, Claisen-Schmidt condensation, one-pot multicomponent reactions (MCRs), reductive amination, Grignard reaction, etc…. Conclusion: Many quinoline ring systems, specifically concerning medicinal chemistry, had been published over the past decade. During this review, we have outlined the synthetic routes and reactions of 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinoline-3-carbaldehydes. This review implies a section of the synthesis of 2-(piperidin-1-yl) and/ or 2-(morpholin-1-yl) quinoline-3-carbaldehydes which can be prepared via Vilsmeier formylation of N-arylacetamides followed by heating of the formed aldehydes with piperidine or morpholine and two sections on its reactions with different reagents were presented. Eventually, this review focus upon 2-(piperidin-1-yl) and/ or 2-(morpholin-1- yl) quinoline-3-carbaldehydes as an interesting heterocyclic compound that can be utilized as a precursor and building block for the synthesis of an extended range of heterocyclic systems which have a potent pharmacological interest.

Hydro-alcoholic extract of Ochradenus baccatus exhibits anti-oxidative and anti-inflammatory properties and inhibits enzyme of uric acid metabolism: Implications for bioactive molecules

Traditional medicines have been an accessible, affordable, and culturally acceptable model of healthcare that is trusted acrossthe globe in terms of disease management, symptoms relief and patient satisfaction. The natural products derived from plant sources arethe fundamental ingredients of traditional and folk medicine and serve as lead compounds or pharmacophore for most effective drugs inmodern pharmacology for treatment of infectious and chronic diseases. Ochradenus baccatus, which belongs to family Resedaceae, is aperennial shrub, widely distributed in the arid regions of Arabian Peninsula and finds mention in the traditional medicine for reproductivehealth, inflammation and infection. Results: As a proof-of-concept, this study has investigated the various bioactive properties of the plantvis-à-vis anti-oxidative, anti-inflammatory and inhibition of xanthine oxidase using standard in vitro experimental models. The bioactivemolecules found in the extract included flavonoids, phenolics, tannins, saponins and alkaloids in varying quantities, which are known tobe associated with a multitude of pharmacological properties. Our results show that the extract caused a progressive inhibition of DPPHradical and neutralizes superoxide anions in a dose-dependent manner. The extract demonstrated its redox-active potential by means of itsability to reduce Cu (II) to Cu (I) that is detected using bathocuproine, a Cu (I)-specific sequestering agent. Progressive doses of the extractsinhibited the denaturation of protein (a factor associated with inflammation), with maximum inhibition of 70.6% observed at concentrationof 600 μg/ml, after which the effect plateaued for further doses. Moreover, the extract displayed a progressive inhibitory property againstthe enzymatic activity of xanthine oxidase with a maximum inhibition of 66% observed at a dose of 300 μg/ml. Conclusion: Inhibition ofxanthine oxidase reduces the hyperuricemia in patients with gout and nephrolithiasis as it alleviates the tendency of salt accumulation inthe joints and kidney. The interest in the natural products pharmacology is escalating and exploring novel bioactive properties in plantsof interest is a significant stride from the traditional knowledge to evidence-based practice

Effectiveness of project-based learning in pharmacology as a teaching learning tool for second MBBS students in a medical college in South India

Background: Being a vast, volatile and dynamic subject, innovative teaching learning methods are required to generate student’s interest in learning Pharmacology. Aims and Objectives: The aim of the study was to study the effectiveness of project-based learning (PBL) program (preparation of a poster or building a model) in improving learning in Pharmacology and to obtain student feedback on the program. Materials and Methods: Twenty-one topics with equal difficulty level were selected from the “must know” portions in Pharmacology. 97 students of second professional MBBS were divided into 12 groups for building a model and nine groups for preparing a poster. Groups for preparing a model had minimum five members and groups for preparing a poster had minimum four members in each group. They were asked to prepare the project based on the topic in 1 month as group task. On the day of the submission, one of the group members presented the model/poster and all other students attended the presentation. A test of ten questions (section A) was done on the students before the presentation which was entirely based on their own project. On the same day, pre-test (section B) having 20 questions, one from each topic was done before the presentation. Post-test was done for all the students immediately after the presentations and also after 1 week. Feedback forms were given to the students after the presentation. Data collected from both the projects were analyzed separately. Results: The improvement in immediate post-test was significant in students involved in both the projects compared to the pretest results. In the individual project assessment, ≥50% marks were scored by 89.8% of the students involved in model building and 87.9% of the students involved in poster preparation. 46 students (78%) involved in model building and 24 students(72.7%)involved in the poster preparation opined that the overall process of preparing and presenting the poster/model was extremely enjoyable. 49 students (83.05%) involved in model building and 28 students (84.8%) involved in poster preparation opined that the project work was extremely helpful in understanding the topic. Conclusion: PBL can be incorporated as a novel teaching learning tool in Pharmacology.

Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties.

Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.

From the Nobel prize for physiology to the new training and competitive paradigm of competitive swimming

Nitric - monoxide is recognized as a molecule with a very simple structure, considered for a long time as an extremely toxic substance. Yet, due to the possibility of endogenous biosynthesis and the variety of biological actions it possesses, today it is considered as paracrine substance of exceptional pharmacological, physiological and pathophysiological interest. Bearing in mind the numerous negative ecological and health effects that it has on the human environment on a daily basis, extremely large initial efforts have been made for decades to suppress it to a certain extent.. However, the discoveries that, in the eighties of the last century, led to new scientific advances in the fields of chemistry, physiology and medicine, led to a stunning conclusion - that the survival of the most dominant species on Earth mostly depends on its (bio)synthesis. Depending on the concentration, it performs a dual role in the vasculature, since in lower concentrations it has the function of an extremely powerful vasodilator, while in the case of high concentrations it performs the role of cytotoxin and cytostatic, thereby contributing to the body's defense against parasitic infections and tumors. Maintaining its availability in the endothelium is crucial for the normal functioning of the cardiovascular system. The Nobel Prize, which was awarded in 1998. for the discovery of the signaling role of nitric oxide in the human body, opened up a series of specific questions, which primarily relate to the place and role of this molecule in various biochemical processes that constantly occur in the human body under different conditions. Accordingly, the theoretical and empirical issues of the role of nitric oxide in swimming, training, and the general health of swimmers (athletes) in water are the subject of this paper.

2-Guanidinobenzazoles as Building Blocks to Afford Biologically Active Derivatives

Abstract: 1,3-Benzazoles (BZs) are interesting compounds in medicinal chemistry. For instance, compounds with the BZ nucleus exhibit diverse biological activities and some of them are broadly utilized in clinical applications. In this sense, medicinal chemists aim at the development of new procedures to synthesize these kinds of molecules. The 2-aminobenzimidazole 2ABI derivatives, such as Enviradine (antiviral), Astemizole (antihistaminic), and Albendazole (antimicrobial), which contain the intra-cyclic guanidine nucleus, are used in medicinal chemistry. The guanidine group, considered a super base, when bonded to a benzazole ring, results in the 2-guanidinobenzazoles (2GBZs), modifying the biological activity of these heterocycles. The structure of 2GBZs is of significance as the 10-π electron system of the aromatic benzazole ring is conjugated with the exocyclic guanidine group to acquire a planar delocalized structure. This class of molecules has at least four nitrogen atoms with free lone pairs and four labile hydrogen atoms, resulting in these compounds having amphoteric character. On the other hand, synthetic chemists have used 2GBZs as a building block to produce derivatives as medicinally important molecules. On these bases, in this work, we prepared a bibliographic review of the methodologies reported in the literature used in the synthesis of 2GBZ derivatives of pharmacological interest. We focused the investigation on 2-guanidinebenzoxazol (2GBO), 2-guanidinebenzothiazol (2GBT) and 2-guanidinebenzimidazole (2GBI) as building blocks. We found that compounds derivatives were N-substituted-2GBZs, 2-(pyrimidyl)-ABZs and 1,3,5-triazino[1,2-a]-BZs, which are described chronologically. This work will help searchers related to bioorganic chemistry, inorganic chemistry, medicinal chemistry and pharmaceutical industry in the recent methodologies to synthetize 2-guanidinobenzazole derivatives to be proposed as materials in the different areas. This topic will provide information on the utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.

Evaluation of in vitro antioxidant, anti-bacterial, cytotoxic and in vivo analgesic and neuro-pharmacological investigation of alysicarpus vaginalis available in Bangladesh

Purpose: The objectives of this research were to investigate the effects of Alysicarpus vaginalis L. (Alyce clover) leaf extracts prepared with ethyl acetate and methanol on in vitro activities like antioxidant, antimicrobial and cytotoxic, as well as on some in vivo activities like analgesic and neuropharmacological properties in an animal model. Study Design: Phytochemical screening was used as the primary method of evaluation for both the ethyl acetate (EAEAV) and methanolic extract (MEAV) of Alysicarpus vaginalis (L.). Because of the pharmacological interest in the plant's constituent components, it was decided to investigate its potential on in vitro activities, such as antioxidant, cytotoxic and antibacterial. Whether or if the observed effects on its in vivo analgesic and neuropharmacological properties in animal models are statistically significant. Place and Duration of Study: This investigation was performed in Laboratory of Phytochemistry and Pharmacology, Department of Pharmacy and Laboratory of Microbiology, Stamford University Bangladesh, Dhaka between June 2022 to October 2022. Methodology: Both EAEAV and MEAV was subjected for phytochemical screening using various test reagent and was also researched for its potential antioxidant, antibacterial, cytotoxic, analgesic, and neuropharmacological effects. The DPPH Free Radical Scavenging Assay, the Disk Diffusion Method and the Brine Shrimp Lethality Bioassay were all used to determine cytotoxic, antimicrobial and antioxidant activity, using different concentrations respectively. Swiss albino mice were subjected to acetic acid-induced writhing and hot plate tests to determine analgesic efficacy. cGMP pathway induced mechanism test was used to confirm the actual analgesic activity. Open field and hole cross tests were used to evaluate locomotor activity as part of the neuropharmacological experiment. Results: Different phytochemical constituent were detected in the experimental result of EAEAV and MEAV's phytochemical screening. MEAV showed highest antioxidant activity with an IC50 value of 34.70 μg/mL where EAEAV showed IC50 value of 12.49 μg/mL and MEAV also showed higher antibacterial activity compared to EAEAV. EAEAV and MEAV showed most notable lethality with LC50 value of 3.89 μg/mL and 8.71 μg/mL compared to the conventional vincristine sulphate's LC50 value in the brine shrimp lethality bioassay. As opposed to this, EAEAV reduced peripheral nociception in the acetic acid-induced writhing nociceptive paradigm, with percent inhibitions of 42.48% and 47.00% where MEAV reduced 40.63% and 51.77% at the aforementioned dosages as opposed to conventional Diclofenac sodium. cGMP pathway mechanism confirmed the % inhibition of pain using both EAEAV which boosted the pain reduction into 59.62% and 71.12%. Additionally, a considerable analgesic effect was seen in the hot plate test. The extract, when compared to the usual Diazepam, was also shown to reduce motor coordination in the Open Field and Hole Cross Tests. Conclusion: These results confirmed the conventional medicine claims of the Alysicarpus vaginalis (L.) plant's therapeutic virtues and suggest potential mechanisms of action.

SH2 Domains: Folding, Binding and Therapeutical Approaches.

SH2 (Src Homology 2) domains are among the best characterized and most studied protein-protein interaction (PPIs) modules able to bind and recognize sequences presenting a phosphorylated tyrosine. This post-translational modification is a key regulator of a plethora of physiological and molecular pathways in the eukaryotic cell, so SH2 domains possess a fundamental role in cell signaling. Consequently, several pathologies arise from the dysregulation of such SH2-domains mediated PPIs. In this review, we recapitulate the current knowledge about the structural, folding stability, and binding properties of SH2 domains and their roles in molecular pathways and pathogenesis. Moreover, we focus attention on the different strategies employed to modulate/inhibit SH2 domains binding. Altogether, the information gathered points to evidence that pharmacological interest in SH2 domains is highly strategic to developing new therapeutics. Moreover, a deeper understanding of the molecular determinants of the thermodynamic stability as well as of the binding properties of SH2 domains appears to be fundamental in order to improve the possibility of preventing their dysregulated interactions.

Palladium-Mediated Synthesis of [Carbonyl-11C]acyl Amidines from Aryl Iodides and Aryl Bromides and Their One-Pot Cyclization to 11C-Labeled Oxadiazoles.

Positron emission tomography (PET) is a highly valuable imaging technique with many clinical applications. The possibility to study physiological and biochemical processes in vivo also makes PET an important tool in drug discovery. Of importance is the possibility of labelling the compound of interest with a positron-emitting radionuclide, such as carbon-11. Carbonylation reactions with [11C]carbon monoxide ([11C]CO) has been used to label a number of molecules containing a carbonyl derivative, such as amides and esters, with carbon-11. Presented herein is the palladium-mediated carbonylative synthesis of [carbonyl-11C]acyl amidines and their subsequent cyclization to 11C-labeled 1,2,4-oxadiazoles. Starting from amidines, [11C]CO, and either aryl iodides or aryl bromides, [carbonyl-11C]acyl amidines were synthesized and isolated in good to very good radiochemical yields (RCY). The 11C-labeled 1,2,4-oxadiazoles were synthesized without the isolation of the intermediate [carbonyl-11C]acyl amidines and isolated in useful RCYs, including the NF-E2-related factor 2 activator DDO-7263. 3-Phenyl-5-(4-tolyl)-1,2,4-(5-11C)oxadiazole was synthesized and isolated with a clinically relevant molar activity. The broadened substrate scope, together with the good RCY and high Am, demonstrates the utility of this method for the incorporation of carbon-11 into acyl amidines and 1,2,4-oxadiazoles, structural motifs of pharmacological interest.

Plant growth regulators induce differential responses on primary and specialized metabolism of Annona emarginata (Annonaceae)

Plants belonging to the Annonaceae family are known to produce several specialized metabolites, including alkaloids and volatiles of pharmacological interest. However, there are no reports on how specialized metabolism (SM) can respond to the exogenous application of plant regulators and how this possible modulation is associated with primary metabolism (PM). Thus, the aim of this work was to evaluate SM and PM responses of Annona emarginata as a function of the application of plant growth regulators. For this, young plants were treated with auxin, methyl jasmonate , salicylic acid and abscisic acid at various concentrations. To know the particular effect of auxin, a second experiment was carried out using auxin and its inhibitor, observing responses at various times after application. SM responses were the quantification of total alkaloids, oxoaporphine liriodenine, number of alkaloids in roots and leaf volatile profile. For PM, gas exchange and chlorophyll a fluorescence variables were determined. Some plant regulators promoted changes over photosynthesis variables in Annona emarginata at specific concentrations and evaluation times; the most pronounced effects were caused by auxin, mainly reduction in net carbon assimilation and less photochemical dissipation at 10 -6 M. The application of 10 -6 M auxin and 10 -3 M salicylic acid in A. emarginata caused increase in total alkaloids and liriodenine. All regulators altered the composition of leaf volatiles, that were reflected in the classes of volatiles or in individual molecules, for example, with auxin, methyl jasmonate and salicylic acid decreasing the relative proportion of monoterpenes, and abscisic acid causing alterations in sesquiterpenes. Thus, it was possible to demonstrate that A. emarginata alters the energy flow between primary and specialized metabolism as a function of the applied plant regulator and that the number and proportion of specialized metabolites are modulated according to the applied plant regulator. • Auxin and salicylic acid caused an increase in alkaloids in A. emarginata. • Auxin, methyl jasmonate, and salicylic acid reduced the monoterpenes hydrocarbons. • Salicylic acid caused an increase in α-humulene sesquiterpene. • A. emarginata modifies the production of alkaloids and VOCs by phytoregulators. • A. emarginata modulates primary and/or secondary metabolism due to phytoregulators.

Divergent Sequential Reactions of β‐(2‐Aminophenyl)‐α,β‐ynones with Malonyl Chloride

AbstractA viable one‐pot synthesis of challenging 4H‐[3,4‐c]quinolone‐4,5(6H)‐diones by the reaction of β‐(2‐aminophenyl)‐α,β‐ynones with ethyl malonyl chloride is described. Their further elaboration in the presence of an excess of 40 % methyl amine aqueous solution in EtOH gives the benzo[c][2,7]naphthyridine‐4,5(3H,6H)‐diones of pharmacological interest in high yields. The product selectivity control of the divergent sequential condensation/C‐annulation/intramolecular transesterification vs condensation/O‐annulation/ring opening reactions of β‐(2‐aminophenyl)‐α,β‐ynones with malonyl chloride under metal free conditions has been addressed.