Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 10th World Congress on Medicinal Chemistry and Drug Design Barcelona, Spain .

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Scientific Program Day 1
Scientific Program Day 2

Day 1 :

Keynote Forum

Celerino Abad-Zapatero

University of Illinois at Chicago (UIC), USA

Keynote: Are SAR tables obsolete?

Time : 10:00-10:35

Biography:

Celerino Abad-Zapatero has completed his PhD as a Molecular Crystallographer at University of Texas at Austin and completed Postdoctoral work on virus and protein crystallography with Prof. M.G. Rossmann at Purdue University in the mid 1980s, solving the structure of the first icosahedral viruses. He worked for over 22 years at Abbott Laboratories employing and developing the tools of macromolecular crystallography for Structure-Based Drug Design (SBDD). His research is focused on the use of alternative variables, in particular ligand efficiency indices to optimize SBDD.

Abstract:

The listing of the structures of compounds possessing biological activity (expressed as Ki, IC50 primarily) (structure-activity tables, SAR tables) for any drug discovery project is the core of any publication accross the medicinal chemistry scientific literature. It has been the standard way of reporting the progress of pharmaceutical discovery since the historical work of Erlich and coworkers in the early 1900'S. This summary was particularly important when the main variable driving drug discovery was potency. Nowadays, drug discovery teams have to examine a large number of variables simultaneously and pay a very close atention to the physicochemical properties (primarly size, polarity/hydrophobicity) of the chemical entities being pursued. Presenting and summarizing all this information in an effective manner is of the utmost importance. ‘Alternative variables combining the affinity of the ligands with relevant physico-chemical properties of the compounds have been introduced in various ways in the literature and are being cited in the literature, particularly as ligand efficiency indices. Controversy over the usage and utility of these variables to drive drug discovery is still prevalent in the community. The presentation will discuss certain formulations of ‘Ligand Efficiency Indices’ that permit the complete mapping of chemico-biological space (CBS) in efficiency planes (AltasCBS: https://www.ebi.ac.uk/chembl/ atlascbs/), which allows a direct two-dimensional representation of the information presented in the SAR tables in a graphic manner. The proposed representation permits an easy and effective understanding of the multiparameter optimization variables involved, and intuitvely suggest the most efficient strategies to optimize the drug-like properties of the compounds.

Keynote Forum

Franz-Josef Meyer-Almes

University of Applied Sciences Darmstadt, Germany

Keynote: Fluorescence lifetime based assays in drug discovery

Time : 10:35-11:10

Biography:

Franz-Josef Meyer-Almes has completed his PhD at the University of Goettingen. He has 10 years of experience in biotech and pharma companies. He is a Professor for Physical Biochemistry and has published more than 40 papers in reputed journals and holds more than 10 patents and patent applications.

Abstract:

High-throughput assays for drug screening applications have to fulfill particular specifications. Besides the capability to identify even compounds with low potency, one of the major issues is to minimize the number of false-positive hits in a screening campaign in order to reduce the logistic effort for the subsequent cherry picking and confirmation procedure. In this respect, fluorescence lifetime (FLT) appears as an ideal readout parameter that is supposed to be robust against autofluorescent and lightabsorbing compounds, the most common source of systematic false positives. The extraordinary fluorescence features of the recently drug discovered [1,3]dioxolo[4,5-f][1,3] benzodioxole dyes were exploited to develop FLT-based binding assays for several bacterial and human isoforms of the histone deacetylase (HDAC) family

Keynote Forum

Barbara De Filippis

University “G. d’Annunzio”, Italy

Keynote: Stilbene-based compounds: from synthesis to biological activities

Time : 11:25-12:00

Biography:

Barbara De Filippis completed her bachelor degree in Pharmaceutical Chemistry and Technology in 1997 and PhD in Medicinal Chemistry at the University of Chieti (Italy) in 2001, and she is currently an Assistant Professor of Medicinal Chemistry in the same university. Her main research topics are related to metabolic diseases and cancer and she has published numerous publications in these fields. Her current research interests have shifted toward the synthesis of resveratrol derivatives useful as potential anticancer and antioxidants.

Abstract:

Stilbene is a versatile scaffold characterized by two aromatic rings linked by an ethylene bridge. Stilbenes are defense compounds produced by some plants in response to pathogen attack and other stresses. Stilbene-containing compounds, as resveratrol, are abundant in natural products, with a variety of important biological activities such as antioxidant, hypolipidemic, antiviral and antiinflammatory. In the last decade, natural compounds with stilbene backbone demonstrated to possess promising activity in cancer prevention, targeting a wide variety of intracellular pathways. In order to overcome the unfavorable pharmacokinetic of resveratrol, different substituents were introduced on one or both aromatic rings and numerous hybrid derivatives have been synthesized and tested on different biological targets. There are clinically used drugs featured by the presence of stilbene nucleus. Starting from these data, our studies explored the potential of synthetic compounds containing the stilbene scaffold (Figure) on crucial biological processes, such as the modulation of PPAR nuclear receptor activities. We further explored the effects of the above mentioned compounds on different pathological processes, including cancer. This talk focuses on the synthesis and biological activities of compounds that contain stilbene:- hybrids constituted by a 4-substituted stilbene moiety and different alkanoic chains, active as
agonists on PPARs and antioxidant on mouse myoblast C2C12 and breast cancer MCF7 cell lines;- stilbene-phenols with different substitution patterns on aromatic rings, active on C2C12 and pancreatic tumor cell lines;- stilbene-sulfonates and sulfonamides potentially active as aromatase inhibitors.

Recent Publications

1. Diaz-Gerevini G T et al. (2016) Beneficial action of resveratrol: How and why? Nutrition 32:174-178.
2. Giacomini E et al. (2016) The Use of stilbene scaffold in medicinal chemistry and multi-target drug design, Current Medicinal Chemistry 23: 2439-2489.
3. De Filippis B et al. (2017) Anticancer activity of stilbene based derivatives, ChemMedChem 12: 1-4.
4. De Filippis B et al. (2015) PPAR agonists based on the stilbene and its bioisosters: biological evaluation and docking studies, Med. Chem. Comm. 6:1513-1517.
5. Leporini L et al. (2017) In vitro protective effects of resveratrol and stilbene alkanoic derivatives on induced oxidative stress on C2C12 and MCF7 cells, J Biol Regul Homeost Agents. 31: 589-601

Keynote Forum

Letizia Giampietro

University “G. d’Annunzio”, Italy

Keynote: Design synthesis and biological evaluation of fibrate analogues as PPAR agonists

Time : 12:00-12:35

Biography:

Letizia Giampietro has completed bachelor’s degree in Pharmacy and received her PhD in Medicinal Chemistry from the University “G. D'Annunzio of Chieti” of Chieti (Italy). From 2006, she is working as an Assistant Professor of Pharmaceutical Analysis. She has published more than 40 papers in reputed journals. Her research interests include Medicinal Chemistry and are above all focused towards the synthesis of fibrate derivatives active on Peroxisome Proliferator-Activate Receptors (PPARs). Lately, her research is directed to the synthesis of small molecules with anticancer, neuroprotective and antioxidant activity

Abstract:

Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors expressed in metabolically active tissues. To date, three isoforms namely PPARα, PPARγ and PPARδ are identified; they are important in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists are able to reduce side effects of selective PPARα or PPARγ agonists and may be used in dyslipidemia and type 2 diabetes mellitus simultaneously. Furthermore, PPARα/γ/δ pan-agonists could alter carbohydrate and lipid metabolism in a coordinated manner. In the last years, PPARs are emerging as promising pharmacological targets also for the treatment of neurodegenerative diseases. Fibrate analogues active as PPAR agonists have, as typical pharmacophore, a carboxylic acid head and an aromatic ring with or without various spacers. In the past, we reported different fibrate analogues with good activation of PPARs. One of the best compounds was a selective PPARγ agonist GL516 (EC50=0.8 μM). This molecule was a potential neuroprotective agent because proved effective in restoring catalase activity reducing reactive oxygen species (ROS) production and decreasing the apoptosis. Another promising molecule was a dual PPARα/γ agonist GL479 (αEC50=0.6μM and γEC50=1.4μM). This compound was crystallized with the PPARα and PPARγ to understand that it occupies the ligand-binding pocket of PPARα and PPARγ in two distinct conformations. In view of these promising results, and in order to gain more insight on the structure-activity relationships, we synthesized new GL479 analogues with different substituents in para to the phenyldiazenyl moiety and with the oxygen of the linker in para to the 2-methyl-2-phenoxypropanoic group. Moreover, to investigate how the azo linker modification influences the activity we synthesized nitro, amino, ureidic, amide and sulfonamide derivatives. All compounds were tested on PPARs and the results showed that some of these are promising candidates to develop new more potent PPAR agonists potentially active as neuroprotective agents.
Recent Publications
1. Den Broeder MJ, Kopylova VA, Kamminga LM and Legler L (2015). Zebrafish as a model to study the role of peroxisome proliferating-activated receptors in adipogenesis and obesity. PPAR Res. 358029.
2. Bordet R, Ouk T, Petrault O, Gele P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart JC and Bastide M (2006) PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem. Soc. Trans., 34: 1341-1346.
3. Giampietro L, D’Angelo L, Giancristofaro A, Ammazzalorso A, De Filippis B, Fantacuzzi M, Linciano P, Maccallini C and Amoroso R (2012) Synthesis and structure–activity relationships of fibrate-based analogues inside PPARs. Bioorg. Med. Chem. Lett. 22:7662-7666.
4. dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I (2015) Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ. J. Struct. Biol. 191:332–340.
 

 

Keynote Forum

Vladimir Potemkin

South Ural State University, Russia

Keynote: CoMIn to molecular interior-quantum and intermolecular potentials based approaches for rational virtual drug design

Time : 12:35-13:10

Biography:

Vladimir Potemkin has completed his PhD at South Ural State University and Postdoctoral studies from Computer Chemistry Center- Erlangen-Nurnberg University, Germany. He is the Head of Laboratory of Computational Modeling of Drugs. He has published more than 80 papers in reputed journals

Abstract:

A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) is proposed in the presentation. The analysis is fulfilled using a lattice construction analogously to other grid-based methods. The further continual elucidation of molecular structure is performed in two ways: in the terms of intermolecular interactions potentials, e.g. a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are known continual functions and their values can be determined in any point of space; in the terms of quantum functions, e.g. electron density, Laplacian, Hamiltonian, potential energy distribution, the highest occupied, the lowest unoccupied orbitals distribution and their superposition. All the functions can be calculated using a quantum approach at a sufficient level in any point of space. To reduce time of calculations using irst principles quantum methods, an original quantum free-orbital approach AlteQ is proposed. Then, the molecules of a dataset can be superimposed in the lattice for the maximal coincidence (or minimal deviations) of the potentials or the quantum functions. Themethods and criteria of the superimposition are discussed. Then, a relationship between bioactivity and characteristics of potentials or functions is created. The methods of the relationship construction are discussed. New approaches for rational drug design based onthe intermolecular potentials and quantum functions are invented. All the invented methods are present at www.chemosophia.com web page.

  • Medicinal Chemistry | Analytical Chemistry | Applications of Organic and Medicinal Chemistry in Drug Discovery | QSAR (Quantitative Structure-Activity Relationship) Fragment-Based Drug Design | Drug Design and Drug Development | Pharmacology and Toxicology
Location: Gatwick

Chair

Letizia Giampietro

University G. d Annunzio, Italy

Co-Chair

Youssef I Moharram

Tanta University, Egypt

Session Introduction

Youssef I Moharram

Tanta University, Egypt

Title: Electrochemical behaviour of duloxetine HCl drug in formulation and spiked human serum at a carbon paste electrode

Time : 14:00-14:25

Biography:

Youssef I Moharram has completed his PhD at Tanta University in Egypt and Leeds University in UK (Channel System). He has published more than 25 papers

Abstract:

The electrochemical behavior of duloxetine HCl (DXT.HCl) drug was investigated. Two precise linear sweep and square wave adsorptive anodic stripping voltammetry methods have been described for its trace quantitation in pharmaceutical formulation and human serum. A mechanism of its oxidation was reported and illustrated. The method shows the development of a sensor for selective and sensitive determination of DXT.HCl. DXT.HCl has been oxidized at a CPE via 2-electron due to oxidation of its secondary amino group. The strong adsorption phenomenon of DXT.HCl can be used as an effective preconcentration step prior to the actual voltammetric quantification of the analyte. Two precise linear sweep and square wave adsorptive anodic stripping voltammetry methods have been described for its trace quantitation in pharmaceutical formulation and human serum. The methods were simple, rapid, and in expensive and sophisticated apparatus or expensive solvents, in comparison with other methods used previously for the study of DXT.HCl. So the proposed method can be used for the routine analysis of DXT.HCl, either alone or in its pharmaceutical formulations. However, the proposed SW-AdASV method has a better detection limit in spiked human serum (LOD=2.1×10−8 mol L−1), therefore it is sensitive enough for assay of DXT.HCl in human plasma of real samples and for pharmacokinetic studies. It can be also recommended for its quantification in quality control and clinical laboratories.

Anna Janas

Adam Mickiewicz University in Poznań, Poland

Title: Synthesis and structure-activity relationship of a new derivatives of 14- and 15-membered macrolide antibiotics containing rebuilt saccharide arms

Time : 14:25-14:50

Biography:

Anna Janas was born in Gniezno, Poland, in 1992. She obtained her B.Sc. from Adam Mickiewicz University in Poznan in 2014 and received her M. Sc. degree at the same institution in 2016. She is currently carrying out her PhD studies in chemistry under the supervision of Prof. Piotr Przybylski at Department of Chemistry, Adam Mickiewicz University. To this date she is a co-author of 2 publications. Her research interests include the synthesis of new derivatives of 14- and 15-membered antibiotics with rebuilt sugar arms, determination of their structures in solution and physicochemical parameters

Abstract:

Macrolide antibiotics are large group of natural products produced by various Streptomyces strains. They are used against various infectious diseases. Macrolides can be classified by a lot of different criteria. One of them is type and size of the macrolide ring and type of saccharide moieties joined to the aglycone ring as e.g. mycaminose, mycarose, cladinose, forosamine, desosamine. These classifications includes mainly lactone macrolides antibiotics, such as 14-membered erythromycins, 15-membered azithromycins and 16-membered leucomycins. The macrolide lactone antibiotics mechanism of action is based on the inhibition of bacterial protein biosynthesis at different stages by reversible binding to the bacterial 50s subunit at the ribosome. In our laboratory we work on new modifications of lactone macrolide antibiotics, of an improved binding profile to biological target and of increased antibacterial potency. Our modifications are performed using cascade and click approaches to enable better matching between antibiotic and target enzyme/protein. Previously, some changes at aglycone ring via complete reconstruction of saccharides parts using regio- and diastereoselective cascade combination of intramolecular esterifications followed by tandem E1cB eliminations and subsequent 1,2-addition to carbonyl followed by 1,6-conjugate addition α, β, γ, δ –unsaturated aglycone led to entirely new series of macrolide antibiotics of antibacterial and anticancer potential. Currently, with the support of Polish National Science Centre (decision number UMO-2015/19/B/ST5/00231), we applying this approach to modification of another group of natural macrolide antibiotics - 15-membered azalides, by rebuilt saccharide arms using Huisgen reactions, to obtain efficient alternatives to the currently used antibiotics (azithromycin) in clinical therapy.

C S Ramaa

Bharati Vidyapeeth’s College of Pharmacy, India

Title: Pyrazoline containing malonyl CoA decarboxylase inhibitors: Design, synthesis and in vitro evaluation

Time : 14:50-15:15

Biography:

C S Ramaa is a Professor and Head of Department of Pharmaceutical Chemistry at Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai. She received her PhD in Pharmaceutical Chemistry from University Department of Chemical Technology. She has been working at Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai. She has received several grants from renowned funding agencies like Department of Science and Technology, Basic Research in Nuclear Sciences, Lady Tata Memorial Trust and University of Mumbai. She has published more than 35 research and review articles in international and national esteemed journals. She has also presented more than 30 presentations at national and international conferences. She has been awarded as Best Research Guide for national level PharmInnova Award.

Abstract:

Introduction: Cardiovascular disease is one of the leading causes of death in the modern world. Impaired cardiac efficiency is an important contributor to the severity of cardiovascular disease. Impaired cardiac efficiency is caused by an inadequatesupply of oxygen to the heart. Malonyl-CoA decarboxylase (MCD) decarboxylates malonyl-CoA to acetyl-CoA. Therefore, the inhibition of MCD increases the level of malonyl-CoA, which further reduces fatty acid oxidation and increases glucose oxidation in the mitochondria. A shift in the mitochondrial metabolism from fatty acid to glucose oxidation increases Adenosine tri phosphate production. Thus, the heart may receive more energy even if the oxygen supply is less. In addition, increased glucose oxidation reduces pyruvate in cellular fluids, improving the pH balance of heart cells. Recently, researchers have synthesized MCD inhibitors based on this novel approach of increasing energy supply to the heart. In the present work series of small molecules (5a–5m, 6a–6j) were schematically designed and synthesized using simple chemical procedures. Their structures were confirmed based upon findings from infrared, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra. The derivatives were evaluated for their in vitro malonyl CoA decarboxylase inhibition activity by using fluorimetric assay. Pyrazol-1-yl-1, 3-thaizol-4(5H)-one derivative (5a–5m) showed better activity than pyrazol-1- yl-1-ethanone derivatives (6a–6j). Compounds 5e, 5j, and 6f showed an excellent in vitro malonyl CoA decarboxylase inhibition activity with IC50 value 0.10, 0.27, and 0.26 μM, respectively. These most active compounds 5e, 5j, and 6f were docked intomalonyl-CoA decarboxylase (HsMCD, PDB ID: 2YGW) to study ligand–protein interaction.

Yanira Méndez Gómez

Leibniz Institute of Plant Biochemistry, Germany

Title: Multicomponent access to conjugate vaccines

Time : 15:15-15:40

Biography:

Yanira Méndez Gómez received her academic education from the University of Havana. Currently, she is a PhD student in the group of Prof B Westermann, IPB, Germany and the group of Prof D G Rivera, CEPN, Cuba. She is dealing with the synthesis and bioconjugation of capsular polysaccharides to carrier proteins and adjuvants to obtain conjugate vaccine candidates. Simultaneusly, she is working as Lecturer in Department of Organic Chemistry at University of Havana.

Abstract:

Though the discovery of antibiotics in the 20th century discouraged the application of carbohydrate based vaccines, the appearance of bacterial resistance and the cuasi prohibitive access to really new antibiotics have turned the interest toward new carbohydrate based vaccines. This work describes the development of a new synthetic strategy towards antibacterial glycoconjugate- and specially multivalent vaccines. The conjugation of functionalized capsular polysaccharides of Streptococcus pneumoniae and Salmonella enterica serovar Typhi to carrier proteins such as diphtheria and tetanus toxoids was caried out via the Ugi 4-component reaction, giving access to mono and multivalent unimolecular glycoconjugates by conjugating them to immunogenic proteins. This gives rise to opportunities toward multivalent and self-adjuvanting vaccines, which will be reported.

Raquel Díaz

Universitat Autònoma de Barcelona, Spain

Title: Recombinant ricin nanoparticles design for CXCR4+ cancer cell therapy

Time : 16:20-16:45

Biography:

Raquel Díaz is studying her PhD program at Univerity Autonomous of Barcelona .

Abstract:

The potent ligand T22, that specifically binds the CXCR4+ receptor, overexpressed in some cancer cells, was engineered to be attached to the N terminus of the mutated A chain of the plant toxin ricin fused to a 6xHis tag in the C-terminus. The soluble recombinant protein T22mRTAH6 spontaneously self assembled as protein-only regular nanoparticles of about 12nm in size, capable of CXCR4 dependent cellular internalization and effective cytotoxic effect in vitro. Meanwhile, the insoluble version of the protein presented moderate free-protein release inducing to a partial cytotoxic effect in the cells. The T22mRTAH6 nanostructured construct was also tried in mouse models of acute myeloid leukemia, where it proved to reduce dramatically the disease affectation of clinically relevant organs. The functionalized protein nanoparticles are then proposed as suitable prototypes for antitumor carcinogenic therapies based on self-mediated intracellular drug delivery.

Bisratewongel Tegegne

Addis Ababa University, Ethiopia

Title: Levels of selected metals in commercially available rice in Ethiopia

Time : 16:45-17:10

Biography:

Bisratewongel Tegegne Alemu done her PhD & MSc. from Analytical Chemistry; Addis Ababa University, she done her BSc. in Applied Chemistry from Haramaya University, she is currently working as teacher in higher education at Bahir Dar University, Bahir Dar (Ethiopia). she received certificate of oral presenter on 4th Annual conference of Society of Ethiopian Women in Science and Technology, and workshop on Empowering Women in Leadership Skill in Science and Technology, April 2018. she also received certificate on Environmental Risk Assessment Management from Africa Center of Excellence for Water Management (ACEWM) Addis Ababa University, Ethiopia. she won Gold Cup award for being the From Haramaya University, Ethiopia, first from the graduated batch in July 2010 

Abstract:

This study reports the levels of metals in commercially available imported (Oryza sativa) and Ethiopian rice(Oryza glaberrima). The levels of thirteen metals (Ca, Mg, K, Na, Fe, Mn, Zn, Cu, Co, Ni, Cr, Cd and Pb) were determined in six varieties of raw rice collected from Addis Ababa supermarkets, Fogera town and Amahara Regional Agricultural Research Institute and in one selected cooked rice by flame atomic absorption spectrometry (FAAS) after digesting the powdered rice samples with HNO3, HClO4 and H2O2 mixture. The validation of optimized digestion procedure was evaluated using spiking method and an acceptable percentage recovery was obtained. The levels of metals found in the imported and Ethiopian rice, respectively, were in the ranges (mg/kg): Ca 75.8-630, 205-427; Mg 90.6-150, 99.5-2250; K 1680-2150, 1100-3020; Na 70.6- 78.6, 26.7-80.9; Fe 48.9-117, 41.3-113; Mn 4.1-15.5, 3.7-16.6; Zn 16.4-25.7, 15.6-140; Cu 2.7-4.9, 3.3-15; Co 12.6-14.6, 8.8-10.4; Ni 2.5-75.1, 41.5-69.7; Cr 2.2-3.12, 2.32-4.82; Cd <0.34, 0.45-2.54; Pb 2.1-5.3, 0.8-3.8. Comparison between levels of metals in the imported and Ethiopian rice showed significant differences for most of the metals. The results indicated that Ethiopian rice is comparatively rich in essential metals than imported. A statistical analysis of variance (ANOVA) at 95% confidence level for metal determination indicated significant difference between the means of each variety of samples. Comparison between levels of metals in cooked and raw rice showed that the difference in the level is not significant

 

Amer Tarawneh

Tafila Technical University, Jordan

Title: Discovery and structure - activity relation study of small-molecule as CB2 selective ligand

Time : 17:10-17:35

Biography:

Abstract:

The CB1 receptor was originally called the cannabinoid receptor before the CB2 receptor was discovered, but CB1 did not explain the immunomodulatory effects of cannabis, which were already well-documented at this time. In 1993, this effect was accounted by the finding of the CB2 receptor in a human promyelocytic leukemia cell line. Both CB1 and CB2 are G-protein coupled receptors, which share a 48% sequence identity. There have been numerous studies on the pharmacology of CB2, giving it the name receptor with an identity crisis. Because CB2 (unlike CB1) is largely not expressed in the central nervous system, but rather in the spleen and immune cells, it is known as the peripheral cannabinoid receptor soon after its discovery. When CB2 expression was found in the neurons and in the microglial cells of the brain, this terminology was determined to be inaccurate, and CB2 expression has since been shown to be correlated with neuroinflammation. A 2005 study showed a 200-fold up regulation of the CB2 receptors in the microglial cells in an in vitro model of autoimmune encephalomyelitis many of these studies are now considered questionable because further research has shown that the anti- CB2 antibodies used in these Immunohistochemical methods have non-specific binding with other proteins. However, the immunomodulatory effects of CB2 remain unchallenged. In addition, CB2 expression has more recently been associated with neurodegenerative diseases such as Huntington and Alzheimer. CB2-selective Positron Emission Tomography (PET) tracers in Alzheimer’s mice have demonstrated increased expression of CB2, concomitant with the formation of amyloid-beta plaques. This suggests that CB2 PET tracers may have potential as a diagnostic tool for neuro-inflammation. In order to counteract these effects, studies are underway to develop selective CB2 ligand. This research began with testing of a series of isoxazole and triazole derivatives, which lead to discovery of a novel ligand highly selective for cannabinoid receptor 2. Compound ATJ-31 produced a concentration-dependent inhibition of specific [3H] - CP55, 940 (CB2) binding with a Ki value of 105 nM, while no binding affinity toward CB1 receptor was observed. The current study aims to design, synthesize and biologically evaluate potential CB2 receptor ligand.
Recent Publications
1. Savonenko A V, Melnikova T, Wang Y, Ravert H, Gao Y, Koppel J, Lee D, Pletnikova O, Cho E, Sayyida N, Hiatt A, Troncoso J, Davies P, Dannals R F, Pomper M G and Horti A G.(2015) Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation. PLoS ONE 10(6):e0129618.
2. Baek J H, Darlington C L, Smith P F and Ashton J C. (2013) Antibody testing for brain immunohistochemistry: Brain immunolabeling for the cannabinoid CB2 receptor. Journal of Neuroscience Methods 216(2):p. 87.
3. Marchalant Y, Brownjohn P W, Bonnet A, Kleffmann T and Ashton J C (2014) Validating Antibodies to the Cannabinoid CB2 Receptor: Antibody Sensitivity Is Not Evidence of Antibody Specificity. Journal of Histochemistry & Cytochemistry. 62(6): p. 395.
4. Di Marzo V, Stella N and Zimmer A (2015) Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci. 16(1): p. 30.
5. Savonenko A V, Melnikova T, Wang Y, Ravert H, Gao Y, Koppel J, Lee D, Pletnikova O, Cho E, Sayyida N, Hiatt A, Troncoso J, Davies P, Dannals R F, Pomper M G and Horti A G (2015) Cannabinoid CB2 Receptors in a Mouse Modelof Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation. PLoS ONE. 10(6): p. e0129618.

 

  • Young Researchers Forum
Location: Gatwick

Session Introduction

Tuvshinjargal Budragchaa

Leibniz Institute of Plant Biochemistry, Germany

Title: Synthesis of α-acylamino and α-acyloxy amide derivatives of desmycosin and evaluation of their antibacterial activities

Time : 12:00-12:20

Biography:

Tuvshinjargal Budragchaa has completed her PhD at the University of Vienna, austria concentrating in Asymmetric synthesis and application of bronsted acid catalysis and their applications. Currently, she is doing her postdoctoral research at the Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, and Halle Saale. She focuses on modification of exisiting macrolide moieties to enhanced antibacterial activities and fine tune the physicochemical profiles as well as modification of plant derived bioactive compounds

Abstract:

Bacterial resistance to the existing drugs requires a constant development of new antibiotics. Especially compounds active against gram-negative bacteria are difficult to target. Most effective in terms of time, effort and success rate is the medicinal chemistry driven development (evolution) based on existing antibiotics. Towards this end, macrolide antibiotics were modified to give new derivatives, aiming for enhanced antibacterial activities and physicochemical profiles. This work describes the structural diversification at the C-20 aldehyde moiety of desmycosin into α-acylamino and α-acyloxy amide functionalities in a very efficient and simple way, using isonitrile mediated multi component reactions. The desired compounds were obtained in 45–93% yield under mild conditions. Antibacterial activities were determined against gram-negative Allivibrio fischeri. The test revealed that the activity is highly dependent on the amine component introduced. Thus, methylamine derived desmycosin bis-amide displayed an enhanced inhibition rate vs. desmycosin (99% vs. 83% at 1 μM). In Ugi reaction, amine and isocyanide components with longer acyclic or bulky substituents reduced potency. In contrast, the carboxylic acids with increased chain length substituents afforded conjugates with increased bioactivity. In Passerini (P-3C) reaction, butyric acid derived α-acyloxy amide showed much better result displaying higher activity (90% at 1 μM) than the reference desmycosin.

Neha Upadhyay

Bharati Vidyapeeth’s College of Pharmacy, India

Title: 5-naphthylidene-2,4-thiazolidinediones: In silico studies, synthesis and primary cytotoxicity evaluation in leukemic cell lines

Time : 12:20-12:40

Biography:

Neha Upadhyay has completed her Post-graduation in Pharmaceutical Chemistry from Bombay College of Pharmacy, Mumbai. She is working as a Junior Research Fellow (JRF) on a project funded by DST, India. She has registered for PhD in Pharmaceutical Sciences at Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, India.

Abstract:

Introduction: Contribution of antidiabetic Thiazolidinediones (TZDs) to cancer therapy has been evidenced by numerous in-vitro and in-vivo studies. While TZDs are known to stimulate PPAR-γ receptor, they also have multiple PPARγ independent effects and the specific role of PPARγ activation in the anticancer effects of TZDs is still under investigation. Also, several reports show the correlation between full activation of PPARγ and associated adverse effects. This prompted us to develop TZD analogues as partial PPARγ agonists and evaluate their anticancer potential.
Methods: We designed series of novel TZDs based on, QSAR model, Docking analysis and Molecular properties study. Further we synthesized and structurally characterized them by 1H-NMR, 13C-NMR, FTIR and Mass spectroscopy. 
Results & Discussion: In the present work, a QSAR model was developed and validated using 25 TZD derivatives synthesized in our laboratory earlier, showing antiproliferative activity against K 562 cell lines, by using experimental and computational study and analysis. The predicted activities by our QSAR models were very close to those experimentally observed, indicating that these models can be safely applied for prediction of more effective hits having the same skeletal framework. We used this model to design new series of 5-naphthylidene-2,4- TZDs and predicted their antiproliferative activity. The molecules from the series, obeying Lipinski’s rule of five were subjected to docking analysis using VLife protocol. The molecules displaying desired interactions as that of partial agonists of PPARγ were further taken for synthesis and evaluated for primary cytotoxic effects on several cancerous cell lines.

Kalpana Tilekar

Bharati Vidyapeeth’s College of Pharmacy, India

Title: Targeting epigenetics: Synthesis and biological evaluation of difluorinated propanediones as HMTase inhibitors

Time : 14:15-14:35

Biography:

Kalpana Tilekar has completed her Post-graduation in Pharmaceutical Chemistry, from Bharati Vidyapeeth’s College of Pharmacy, Mumbai. She worked as an Assistant Professor at NCRD’s Sterling Institute of Pharmacy, Navi Mumbai, India. Currently, she is working as Junior Research Fellow (JRF) on a project funded by DST, India and she is registered for PhD in Pharmaceutical Sciences at Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, India.

Abstract:

Introduction: Pharmaco-epigenomics constitute the hope for a new strategy in cancer treatment owing to epigenetic deregulation, a reversible process, suspected of playing a role in malignancy 30 years prior to the sequencing of the human genome. In this field, several enzymes like HDACs, DNA methyl transferases (DNMTs) and histone methyl transferases (HMTase) have been studied extensively for their capability to be inherited by natural or synthetic compounds. To date, HDAC and DNMT inhibitors are used in cancer therapy are tested in clinical studies. In contrast to this, the search for inhibitors of HMTase is still in its infancy and in-vivo data of most of the agents are not available.
 
Methods: In this research work, we synthesized few difluorinated propanediones and their structures were determined by analytical and spectral (FTIR, 1H NMR, 13C NMR) methods. The newly synthesized compounds were first evaluated for their antiproliferative activity and then for HTMase inhibitory potential in leukemic cell lines. We have also performed cell cycle analysis to study cell growth arrest.
 
Results: Amongst all the synthesized compounds, PR-4 was found to be most active. In the cytotoxicity assay, it showed cell growth of 42.6 % and 53.4% comparable to that of adriamycin; 44.5% and 53.2% in U937 and JURKAT, respectively. At a concentration of 1 and 10μM, it had shown to alter the methylation levels in two leukemic cell lines of histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT). Cell growth arrest was found in the G0/G1 phase in both the cell lines. Discussion: The apoptosis pattern suggests that the molecule PR-4 could emerge as a potential anticancer agent by targeting
HMTases.

Galina Karabanovich

Charles University, Czech Republic

Title: Development of 3, 5-dinitrophenyl containing heterocycles: Structure-antimycobacterial activity relationships studies

Time : 14:35-14:55

Biography:

Galina Karabanovich has completed her PhD at the Faculty of Pharmacy in Hradec Kralove, Charles University. Currently, she occupies the Postdoctoral position at the same University. She has published 12 papers, majority of them in medicinal chemistry journals. Her research interests are focused on the design and synthesis of compounds with potential antimycobacterial activity; study of the relationships between structure and antimycobacterial activity of prepared substances; synthesis of dexrazoxane analogues.

Abstract:

Our research focuses on the design and synthesis of novel nitro group containing heterocyclic compounds with high and selective antimycobacterial efficiency and on the study of relationships between their structure and antimycobacterial activities/toxicities. Previously described 1-alkyl-5-(3,5-dinitrobenzyl)sulfanyl-1H-tetrazoles and 2-alkyl-5-(3,5-dinitrobenzyl) sulfanyl-1,3,4-oxadiazoles showed outstanding activities against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis (M. tuberculosis.). Their minimum inhibitory concentrations reached 0.5 μm and 0.03 μm, respectively.
Moreover, 1, 3, 4-oxadiazole derivatives were active against replicating and nonreplicating strains of z. Described compounds demonstrated selective effect on mycobacteria as were inactive against tested fungi and bacteria and exhibited low in vitro genotoxicity and toxicity in mammalian cell lines. Current work continues to study the role of individual fragments of previously described molecules in their biological properties. We focused on influence of the heterocycle and Benzylsulfonyl linker on antimycobacterial activity. Results of in vitro evaluation showed that both fragments play a significant role in theantimycobacterial efficacy of target compounds. Moreover, alkyl/aryl substituents on heterocycle could also affect compounds efficacy.

Amr Elagamy

University of Delhi, India

Title: Synthesis of highly functionalized spirocyclic butenolides via ring contraction of fused 2H-pyran-2-ones

Time : 14:55-15:15

Biography:

Amr Elagamy has completed his Bachelor of Science in Chemistry at the Faculty of Science, Tanta University, Egypt, and Master degree in Organic Chemistry at Kirori Mal College, University of Delhi, New Delhi, India. He was awarded DBT-TWAS Postgraduate Fellowship in 2015 to complete his PhD in Organic Chemistry at the University of Delhi, New Delhi – India.

Abstract:

Butenolides are a class of lactones, considered as oxidized derivatives of furan with structure made of four carbon heterocyclic ring called furan-2(5H)-ones. A broad range of natural products and biologically active compounds contain butenolides structural as subunits. These compounds exhibit various biological activities such as anti-inflammatory, anticancer, antimicrobial, antifungal, and anti-viral HIV-1. A new method for synthesis of highly functionalized spirocyclic butenolides was achieved through ring opening and relactonization at C5 of fused 2H-pyran-2-ones using nitroalkane as a carbanion source. Nitroethane provides (E)-and (Z)-isomer of spirocyclic butenolides in a ratio of almost 2:1 with relatively better yields than in case of nitromethane which provides only one isomer. Moreover, spirocyclic butenolides obtained from nitroethane undergoes decarboxylative rearrangement in presence of sodium ethoxide to give only one isomer of triene and might be used as a valuable intermediate for synthesis of various triene compounds.