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Consideration of the stereochemical features of compounds in QSAR models. 2D+0.X molecular descriptors.
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

Introduction: In chemoinformatics, stereochemical attributes are commonly taken into account only by direct description of spatial structures via 3D-QSAR approaches.  Usually these models are applied for one fixed conformer of each molecule. That can be undesirable if we don’t know the spatial structure of the molecule interacting with a biological target. In this study we show how to solve this problem in terms of simplex representation of the molecular structure (SiRMS).

Methods: In the SiRMS approach, every molecule is represented as a system of different simplexes (tetratomic fragments with fixed composition and structure). The advantages of that approach are the absence of "molecular alignment" problems, consideration of different physical-chemical properties of atoms (e.g. charge, lipophilicity, etc.), the high adequacy and good interpretability of obtained models and clear ways for  further molecular design. In this study, all molecular fragments which don’t determine stereochemistry of a molecule are described in terms of 2D molecular representation (structural formula). Structural elements which determine molecular stereoisomerism are described by  respective 3D chiral  conformation-independent simplexes  It should be noted that chiral simplexes allow us to describe the molecular system of any stereochemical complexity. In the proposal (2.0+0.X)D - QSAR approach parameter (0.X) is determined by the ratio of 2D achiral and 3D chiral simplexes included in the appropriate QSAR model. 

Results:To evaluate applicability of this approach, we had to solve some QSAR tasks with sets of compounds containing chirality. This approach allowed us to get valid QSAR models for data sets consisting of only compounds with one or more centers of chirality, of chiral and achiral compounds and of compounds with central and axial chirality as well. Use of simplex descriptors also allowed us to get structural and functional interpretation for those models. There was no situation where consensus QSAR model did not include some chiral descriptors, so, all of the studied properties are chirality-dependent.

Conclusion: Quality of those models is an evidence that  application of Simplex Representation of the Molecular Structure with described modification considering chirality is relatively simple and universal approach for obtaining adequate QSAR-models of chirality-dependent properties.

  • Open access
  • 64 Reads
Chemical and Biological Characterizations of an Effective Bimodal Probe to Target Apoptosis
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1


AGuIX® nanoparticles are small platforms of polysiloxane recently developed for various applications of medical imaging. These nanoparticles contain on their surface several amine functions used for the fixation of DOTA ligands. Approximately 70 percents of these ligands are complexed with Gd3+ ions [1]. These paramagnetic platforms have a diameter less than 5 nm and a low transmetalation [2]. Different studies have been achieved in the biomedical domain, showing that they allow to combine multimodal and theranostic properties. A passive tumoral targeting has already been observed by EPR effect (Enhanced Permeation Effect). Otherwise, their small size allows a quick elimination by the kidney [3]. Previous phage display studies showed that TLVSSL peptide has a high affinity for phosphatidylserine, a phospholipid overexpressed on the membrane of apoptotic cells. Apoptosis is a natural process of cell death [4]. The targeting of apoptotic cells is interesting to follow the efficiency of an antitumoral therapy and for diagnosis of diseases related to this process. In this work, AGuIX nanoparticles have thus been grafted with this peptide and characterized.


The TLVSSL peptide has been grafted on nanoparticles AGuIX® by activation with EDC of carboxylic functions available on nanoparticle surface. Furthermore, previous addition of an optical dye allows their applications in optical imaging. Different techniques such as PCS, fluorescence spectroscopy, HPLC and proton relaxometry were used to characterize this platform.


Relaxometric studies by NMRD profiles confirm the increase of the rotational correlation time after linking of the peptide and allow to study the time stability of the platform. The biological efficiency of this novel bimodal agent to target apoptotic cells was evaluated by fluorescence microscopy on lymphablastic human T cell line. In vitro cell apoptosis was chemically induced by incubation with campthothecin. Biological experiments has been checked by fluorescence microscopy and flow cytometry on incubated cells with labelled and grafted-AGuIX nanoparticles. RITC fluorescence intensity detection allowed to confirm the probe efficiency to target apoptosis.


These characterizations and biological tests confirm the binding of the peptide and the efficient targeting of apoptotic cells. Further in vivo tests will be achieved to confirm the efficiency of grafted-nanoparticles on apoptotic mouse model.




[1] F. Lux et Al., Angew. Chem. Int. Ed. 2011, 50, 1-6.

[2] A. Mignot et Al., Chem. Eur. J., 2013, 19, 6122-6136.

[3] G. Le Duc et Al., ACS Nano, 2011, 5, 9566-9574.

[4] C. Laumonier, thesis, 2005, Université de Mons-Hainaut, « Imagerie moléculaire : recherche de vecteurs peptidiques spécifiques de l'apoptose par la méthode du phage display ».

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  • 65 Reads
Biochemical link between chromogranin A and cyclooxygenase-2 in pheochromocytoma pathology
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

The precise biological function of elevated chromogranin A (CgA) in neuroendocrine and nonneuroendocrine neoplasms remains unclear. Limited studies in cell and animal models have provided contradictory evidence as to whether CgA promotes or inhibits tumorigenesis. In a neuroendocrine tumor (NET)-derived cell line a study demonstrated that cyclooxygenase-2 (Cox-2) up-regulates both CgA expression and bioactivity with implications of this polypeptide in neuroendocrine cancer.                      

In our study, we indirectly tested the link between Cox-2 and CgA  in  a  lot of 15 patients clinically suspected of pheochromocytoma by comparison with a lot of 15 matched controls without endocrine dysfunction. Biochemical diagnosis of pheochromocytoma was realized by differentially Elisa assay of plasma free normetanephrines (NMNp) /free metanephrines (MNp) and by plasma Elisa assay of CgA. Plasma Cox-2 was assayed by an Elisa research kit. All four parameters were assayed both in tumoral and normal subjects.We calculated means and standard errors in pheo group vs control subjects and we established statistically significant differences between all parameters assayed. Multiple regression showed important correlation coefficients between: NMNp/CgA: 0.86; NMNp/MNp:0.70; CgA/Cox-2:0.56. Practically,we proved the traffic control of the noradrenergic metabolite NMNp by CgA and Cox-2.Using Relative Operating Curve Analysis (ROC) we compared sensitivity and specificity of all four assayed parameters. Cox-2,CgA,NMNp proved the best sensitivity and a great specificity.                                                                                                                                                      

We can conclude that Cox-2 could be used as a prediction marker in pheochromocytoma pathology together with CgA/NMNp/MNp.


1-Cox-2 promotes CgA expression and bioactivity:evidence for a Prostaglandin E2 dependent  mechanism and bioactivity:evidence for a Prostaglandin E2 dependent mechanism and the    involvement of a proximal cyclic Adenosine 5'-Monophosphate-Responsive Element-Endocrinology 148(9):4310-4317,2007 - Connolly R et al.                                                                

2-Increased expression of cyclooxygenase-2 in malignant pheochromocytomas-J Clin Endocrinol Metab 86:5615-5619-2001- Salmenkiwi K. et al.

3-Pheochromocytoma-Lancet 366:665-675-2005 -Lenders JWM et al.

  • Open access
  • 98 Reads
Microwave-assisted C-H arylation of Quinazolin-4-one-type Precursors of Bioactive Heterocycles
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

Our group is focused on the synthesis of C,N,S- or C,N,O-containing heterocyclic precursors of bioactive molecules able to modulate the activity of kinases involved to some extent in Alzheimer's disease.1 Previous biological results lead us to intensively study thiazoloquinazolin-4-one backbone especially modulations of positions 1 and 2. Following our effort for the construction of a broad range of substituted thiazoloquinazolin-4-one derivatives as potential kinase inhibitors,2 modulating the position 3 was further explored. As an efficient and versatile approach in complex molecules synthesis palladium-catalyzed, C–H functionalization of heteroarenes3 represents an extremely attractive approach.

Our presentation describes the first extensive study of palladium-catalyzed direct C-H (hetero)-arylation of quinazolin-4(3H)-ones with aryl iodides, bromides and chlorides under microwave irradiation.4 This innovative methodology tolerates a broad range of heteroaryl and aryl halides substituted by electronically different groups. The scope of substrates was extended to pyridinopyrimidin-4-ones. This method provides an efficient, versatile, and rapid access to 2-arylquinazolin-4-one backbone and will be extended to our thiazoloquinazolin-4-one derivatives.


  1. (a) Schmitt, C.; Miralinaghi, P.; Mariano, M.; Hartmann, R.W. ; Engel, M. ACS Med. Chem. Lett. 2014, 5, 963. (b) Dehbi, O.; Tikad, A.; Bourg, S.; Bonnet, P.; Lozach, O.; Meijer, L.; Aadil, M.; Akssira, M.; Guillaumet, G.; Routier, S. Eur. J. Med. Chem. 2014, 80, 352.
  2. (a) Foucourt A.; Hédou, D.; Dubouilh-Benard, C.; Girard, A.; Taverne, T.; Désiré, L.; Casagrande, A.-S.; Leblond, B.; Loaëc, N.; Meijer, L.; Besson, T. Molecules 2014, 19, 15546. (b) Foucourt A.; Hédou, D.; Dubouilh-Benard, C.; Girard, A.; Taverne, T.; Casagrande, A.-S.; Désiré, L.; Leblond, B.; Besson, T. Molecules 2014, 19, 15411. (c) Deau, E.; Hédou, D.; Chosson, E.; Levacher, V.; Besson. T. Tetrahedron Letters 2013, 54, 3518. (d) C. Schmitt, P. Miralinaghi, M. Mariano, R.W. Hartmann, M. Engel, ACS Med. Chem. Lett. 2014, 5, 963.
  3. (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17. (b) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960. (d) Ackermann, L. Chem. Rev. 2011, 111, 1315.
  4. (a) Laclef, S.; Harari, M.; Godeau, J.; Schmitz-Afonso, I.; Bischoff, L.; Hoarau, C.; Levacher, V.; Fruit, C.; Besson, T. Org. Lett. 2015, 17, 1700. (b) Godeau, J.; Harari, M.; Laclef, S.; Deau, E.; Fruit, C.; Besson, T. Eur. J. Org. Chem. 2015, in press.
  • Open access
  • 235 Reads
Recycling of Drugs from Expired Drug Products
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

The expiration date is the final day that the manufacturer guarantees the full potency and safety of a medication. In general, most drug products are not toxic when expired but they can lose their effectiveness over time. The decrease in the concentration of the drug in a drug product from 100% to 90% is known as its shelf life. When a medication is used within its shelf life, it shows maximum efficacy and safety.  Recently studies conducted by the U.S. Food and Drug Administration over 100 drugs, prescriptions and over-the-counter products, showed that about 90% of them were effective and safe as long as 15 years past their expiration dates. India's pharmaceutical industry is losing around Rs 500 corer annually on account of destruction of expired drugs, hitting the bottom line of drug manufacturers, especially the small and medium ones. In our present communication, we made an attempt to study different methodologies for recycling active drugs from expired drug products or pharmaceutical dosage forms. It is admitted that when a drug product gets expired, it may contain 90% or even above of the Active Pharmaceutical Ingredient(s). Suitable chromatographic methods and analytical techniques could therefore be adopted for isolation and eventual quantification of active ingredients for the purpose of successful recycling (especially if manufacturers are mandated to blister-package and bar-code for individual tablets and capsules) into useful synthetic intermediates or active drugs. This approach would remain cost-effective as well as eco-friendly from the point of view of its industrial applicability.

  • Open access
  • 296 Reads
Complex of zinc and lectins from seeds of Vigna radiata as potential anti-diabetic agent
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1


Proteins and phytohemagglutinins from Vigna species have been known to possess α-amylase inhibitory activity. Therefore, it was thought worthwhile to evaluate the lectins from Vigna radiata for antidiabetic activity. The literature reveals that such studies have not yet been carried out. The principal object of this study  is to evaluate antidiabetic activity of the lectins from V. radiata. Another object of this study  is binding of the zinc with the lectins obtained from V. radiata and evaluation of its antidiabetic activity.


 The V. radiata seed found contain galactose specific lectin.  The MBL-I (Mung Bean Lectin I ) may be a tetrameric protein with molecular weight 160-180 kDa and may be composed of identical or nearly identical relative subunit of molecular weight of 45-50 kDa.  Amino acid analysis of purified Mung bean lectin by reverse phase HPLC revealed that, it contains Glutamate in highest proportion followed by Aspartate and also contains Histidine, which indicates it has good zinc binding potential Binding of the lectins with zinc improved overall stability and efficacy of the lectins.  The antidiabetic acativity was evaluated in Wistar rats using alloxan induced diabetic model and the studies indicated significant (P<0.001) reduction in elevated sugar levels. It’s probable mechanism of antidiabetic action may be insulinomimetic, since, it was found to bind with insulin antibodies in Western Blotting Analysis    


The lectin obtained from V. radiata seed and zinc lectin complex has good potential to be explored as a safe natural antidiabetic agent acting with controlled reduction in blood glucose levels. These findings indicates that the mungbean lectins and zinc lectins complex have tremendous medicinal potential as a herbal antidiabetic drug which need to be explored.

  • Open access
  • 140 Reads
Analgesic and anti-Inflammatory Activity of Diterpenoid Alkaloids Isolated from the Central Asian Species of Aconitum and Delphinium Plants
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

In different countries of Europe, Asia and America the plants containing diterpenoid alkaloids have been used on the folk medicine from ancient time. Aconitum and Delphinium plants (Ranunculaceae family) and their extracts are used in the Eastern medicine at present as antirheumatic, analgesic, anti-inflammatory and other remedies. More 50 species of Aconitum (300 worlwide) and 100 species of Delphinium (450 worldwide) are growing on the territory of Former Soviet Union countries, including Russia, Central Asia and Kazakhstan. 

We investigated analgesic and anti-inflammatory activity of individual diterpenoid alkaloids isolated from Aconitum and Delphinium species widespread in the Central Asia and revealed 25 promising substances. Analgesic activity was investigated in the conventional tests for displaying analgesics with central mechanisms of analgesia (hot plate) and peripheral mechanisms (acetic writhing). Anti-inflammatory activity was studied in rat formalin test. 

By comparison of analgesic activity of investigated alkaloids and underly mechanisms of their pharmacological action we divided them on the following types: activators of potential-gated Na+-channels of neurons cause shifting of the threshold of Na+-current towards membrane hyperpolarization and destroy neuronal conductivity; blockers of potential-gated Na+-channels cause inhibition of the fast intake Na+-current without changing of its activation threshold; blockers of N-cholinoreceptors.

  • Open access
  • 63 Reads
Design, Synthesis and Activity Evaluation of New Irreversible Myeloperoxidase Inhibitors Derived From Benzodioxole
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

The essential role of Myeloperoxidase (MPO) in the immunity system is the oxidation of the pathogenic agents inside the neutrophils. In some cases, this enzyme causes oxidative damages for the host tissues contributing in the development of inflammatory syndromes. Thus, the inhibition of MPO in the circulation can be useful in the treatment of several inflammatory diseases. In the last decade, we described some potent reversible MPO inhibitors derived from fluorotryptamine. In addition we have reported that the SSRI agent (paroxetine) can irreversibly inhibit MPO at low nanomolar range. With the docking experiments, the important chemical groups in both paroxetine and fluorotryptamine derivatives were determined and general structure of the new series was designed.

After determination of the general structure, several modifications, including the length of the side chain, the functional group, the aromatic ring and the dioxole group, were applied to study the SAR of this series. Docking experiments for these designed compounds indicated that the length of the side chain must be between 3 and 6 carbons, the functional groups must be amine or amide, the best aromatic group is benzene and two hydroxyl groups give the compound an interaction with active site higher than dioxole.

These compounds were synthesized and tested in vitro by taurine chloramine test in order to determine the IC50 values. The results confirmed the docking test for several compounds where it is found that the IC50 of the compounds with amine are the lowest values among all the functional groups (IC50= 10-60 nM). It is shown also that 5 carbons on the side chain give the best activity for the compounds with amine while those of amide the best activity was in the compound with 3 carbons. Unlike the docking, the in vitro test showed that the compound with 2 OH instead of dioxole hasn’t any activity. Kinetic study showed that all of the active compounds reduced the Compound I of MPO (MPO-Porphyrin•+-Fe(IV)=O) to the inactive form Compound II (MPO-Porphyrin-Fe(IV)=O) in very fast way. Where Compound I of MPO is the oxidized form that reacts with the halogen ions to give HOX. Then the inhibitor reacts irreversibly with the enzyme causing destruction of the heme. The compound with 2 OH reacts with both Compounds I and II in very fast way to regenerate the native enzyme which in turn is oxidized to Compound I that produces HOCl (the active oxidative molecule of MPO).  

  • Open access
  • 149 Reads
Ebola Virus Disease: Questions, Ideas, Hypotheses and Models
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

How is Ebola virus disease (EVD) contagious? What does it happen at the host-pathogen interface? Why are certain viruses capable of jumping to new species? The genetic plasticity is key if the virus is to overcome a host immune attack. Double-stranded ribonucleic acid (dsRNA) triggers release of cytokines. What is the possibility of an outbreak in Spain? What is the alert level that can have a country as Spain? Does the Law of Labour Risks observe the protocol? In Spain, are there the equipment and experience needed to treat EVD patients? Why is it difficult to control determined infections or find vaccines vs. virus-caused diseases? The double level: Must one be critical with the protocols followed by the Spanish Government? The model of Ebola virus transmission dynamics is reviewed, with the aim to provide a broad sketch of the fundamental human–Ebola-virus biophysical forces that enable and constrain EVD. Akhtar et al. reported a model of Ebola evading the immune system. What are the factors of the emergence, rapid spread and uncontrolled nature of 2014 virus outbreak? How to treat EVD? How does the Ebola virus replicate? Why have bats evolve to resist fatality in the face of the Ebola virus? How have bats evolve to resist fatality in the face of the Ebola virus? Did Ebola Zaire either exist in the African landscape before 1976, or evade detection and documentation? How does Ebola evade the immune system? Provisional conclusions follow. (1) How little one knows about how viruses interact with the human immune system. (2) Transmission among humans occurs via the exchange of blood and body secretions.

  • Open access
  • 88 Reads
Looking for a PET Tracer for Imaging Apoptosis
Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

In multicellular organisms, homeostasis is maintained by a balance between cell proliferation and apoptosis (programmed cell death). It is a physiological form of cell death responsible for the deletion of non-repairable damaged, mutated, or cells which have lost their function.

We describe the synthesis of a series of potential inhibitors of caspases from a modified aspartic acid residue (fluoromethylketone, fmk). The addition to the entire series of, 3-cyano-4-fluoro-benzoyl- pattern on one hand or of, 4-fluoro-2-thiazolamino- pattern on the other hand will subsequently allow the introduction of a PET isotope (18F).

In order to determine potential candidates, the inhibitory activity of these compounds was evaluated in vitro on a series of human T cells compared to the z-VAD-fmk as a reference.