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Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Casein kinase 2 is a ubiquitous kinase protein emerging as a target for the treatment of cancer. Several active CK2 inhibitors have been developed in the last few years; most of them have ATP-competitive type of inhibition. Indenoindoles present a class of natural and synthetic compounds; many of them have different bioactivity. Here we report on the development of a ligand-based pharmacophore on the basis of different active indenoindoles (training set), the pharmacophore model was challenged against small library of indenoindoles (test set), the study was performed using MOE software. Our model demonstrates good performance in the test set, 85% of the medium or high inhibitory activity compounds were identified, while only 17% of the low or no inhibitory activity compounds were misclassified. Several structures were suggested as possible active CK2 inhibitors by using this model as a base for search in the ZINC database among them was bikaverin which was then further studied.

  • Open access
  • 222 Reads
Dual Anti-Inflammatory and Anti-Bacterial Effects of Phenylhydrazide and Phenylhydrazone Derivatives
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to the propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. The implementation of dynamic combinatorial libraries allowed to obtain several compounds derived from aromatic hydrazone with high activity on MPO. These inhibitors were found to be reversible and irreversible MPO inhibitors at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. In vivo evaluation in rats injected by carrageenan showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.

On the other hand, paroxetine and p-aminobenzoic acid hydrazide are irreversible MPO inhibitors. The hydrazide group was identified as responsible for the irreversible activity. In addition, hydroxamic acid derivatives are good reversible inhibitors and the hydroxamate group is very similar to the hydrazide one in electronic density and ability to make bonds. Thus, starting from paroxetine, benzoic acid hydrazide, and hydroxamic acid, a new series of compounds has been  designed and synthesized. These compounds have shown very high activity on MPO with IC50 of 12-900 nM. Investigations on the mechanism of action has demonstrated that these compounds are irreversible MPO inhibitors. To see if these inhibitors impair the innate immunity, the effect of the compounds were tested on the neutrophils. The results showed that these inhibitors inhibit only the released MPO into the extracellular fluids.

Finally, hydrazide and hydrazine derivatives were tested as anti-bacterial agents. Surprisingly, all hydrazone derivatives showed high activity against Gram (-) bacteria and low activity on Gram (+). In contrast, hydrazide derivatives showed very high potency against Gram (+) but no effect was found on Gram (-).

  • Open access
  • 81 Reads
Display of a Full Length IgG Antibody on the Surface of Escherichia coli: Towards the Screening of an Antibody Library
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

In today’s clinical practice, monoclonal antibodies have become a well-established therapy option for a range of indications, such as cancer and autoimmune diseases [1]. To develop various specific antibodies, huge antibody libraries have to be screened. For this purpose phage display has been used with great success in the last 25 years. Nevertheless, this method is associated with some drawbacks as the possible discrimination of the most potent binders during the biopanning process, the incompatibility with flow cytometry or the size limitation of the protein displayed on the surface [2]. To circumvent these disadvantages, we developed a screening tool using E. coli cells presenting a full-length antibody on their surface. The presentation of antibodies and in particular their libraries enables the screening for new variants against pre-given epitopes using flow-cytometry without losing the highly potent binders.

In this work, the autodisplay technique [3,4] was utilized to present a functional full-length antibody on the surface. As a proof of principle, the display of the antibody T84.66 which is directed against carcinoembryonic antigen (CEA) was investigated. Based on this antibody a library was generated. Therefore, restriction sites were introduced in front of and behind the complementarity determining region 3 (CDR3). This enables the exchange of the CDR3 through a randomized fragment. After ligation, this construct was used to transform E. coli UT5600 (DE3) via electroporation. The resulting library consists of up to 105 clones which can be analysed and sorted via flow cytometry after incubation with a fluorescently labelled target protein. To examine the optimal conditions for the screening, two different autotransporters in combination with two promoters were investigated: the AIDA‑1 autotransporter [3] under control of a T7-promoter and the EhaA‑autotransporter [4] controlled by an araBAD promoter. Experiments with the T84.66 antibody as a passenger revealed that the EhaA‑autotransporter under araBAD control suited better with regard to surface presentation and cell survival after sorting via flow cytometry.

These results indicate that it is possible to generate a full-length antibody library on the surface of E. coli which afterwards can be screened with the advantageous high-throughput screening system of flow cytometry. Further investigations should be performed to identify an antibody variant out of the constructed library which binds a pre‑given epitope of therapeutical interest.


  1. Weiner L. M. et al.: Nat Rev Immunol 2010, 10(5): 317-327
  2. Levin A. M., Weiss G.A.: Mol. BioSyst 2006, 2: 49-57
  3. Jose J., Meyer T.F.: Microbiol. Mol. Biol. Rev., 2007, 71(4): 600-619
  4. Sichwart S. et al.: Food Technol. Biotechnol. 2015, 53(3): 251-260


  • Open access
  • 122 Reads
Study of Interactions between D-Mannitol and Polynucleotides
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Background. Complexes of oligoribonucleotides with D-mannitol are highly effective, non-toxic and possess a wide range of biological effects. In particular, such complexes can increase immune reactivity and have antiviral and anti-inflammatory activity. Oligonucleotides without D-mannitol do not have such biological effects.

Methods. Spectroscopy of circular dichroism, absorption spectroscopy, fluorescence spectroscopy.

Results. During the research, we have observed the decrease of fluorescence intensity of the dye water solution with polyribonucleosides. An additional decrease of intensity was observed in complexes with D – mannitol. The maximum effect was obtained for fluorescent sensor solution with polyadenylate and polycytosine. In the cases of polyguanilate and polyuridine minimum changes were observed.  The spectral effect may indicate a more intense interaction between polyadenylate and polycytosine with D-mannitol.

Linear absorption was carried out in the temperature range from 25°C to 60°C. We recorded an increase of the magnitude of absorption of the polynucleotides when increasing the temperature in the cases of polyadenylate and polycytosine. The value of the hyperchromic effect is 10% for polyadenylate, and 5% for polycytosine. Additional increase of the amount of hyperchromic effect was recorded in complexes with D¬-mannitol. Circular dichroism spectroscopy has shown spectra with a large difference in the structure of polyadenylate and polycytosine when compared with their complexes with D-mannitol. In the cases of polyguanilate and polyuridine and their complexes with D-mannitol, we observed no change in structure. Based on quantum-chemical calculations, it was established that hydrogen bonds between D-mannitol and polynucleotides can be generated. Also, calculations indicated appreciable changes in charge distribution especially at atoms that can generate hydrogen bonds.

Conclusion. The obtained data allow us to assume the presence of an additional D-mannitol helix in the complexes of polynucleotides with D-mannitol. This assumption is also confirmed by the simulation of this complexes with the help of the program package Gaussian 09. That can explained the wide spectrum of antiviral action of the complexes of polynucleotides and D-mannitol against both single and two-spiral viruses.

  • Open access
  • 118 Reads
SAR Studies for the in-silico Prediction of HIV-1 Inhibitors
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Tetrahydroimidazo[4,5,1jk][1,4]benzodiazepines (TIBO), as non-nucleoside analogues, constitute potent inhibitors of HIV-1 reverse transcriptase. In the present study, classification structure-activity relationship (SAR) models are developed to distinguish between high and low anti-HIV-1 inhibitors in this class of compounds. Different classifiers, such as support vector machines, artificial neural networks, random forests and decision trees have been established by using ten molecular descriptors. All models were validated using several strategies: internal validation, Y-randomization, and external validation. The correct classification rate ranges from 97% to 100% and from 70% to 90% for the training and test sets, respectively. A comparison between all methods was done in order to evaluate their performances. The contribution of each descriptor was evaluated to understand the forces governing the activity of this class of compounds.

  • Open access
  • 146 Reads
Antidepressive Activity of a Series of Tetrahydropyrido[2,1-B][1,3,5]thiadiazine Derivatives in Forced Swimming Test by Porsolt
, ,
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Background. Studies conducted in the past two decades in different countries have shown that depression is common in the practice of therapist. The prevalence of depressive disorders depends on the country and residence region, but the average estimates suggest that depression occurs in 10-20% of patients of primary health care [1]. It has been shown that the risk of coronary heart disease and stroke is increased in patients with depression [2, 3].

[1,3,5]-Thiadiazine derivatives are characterized by significant biological activities [4-8]. Some compounds of this group of substances exhibited significant analeptic activity on the model "thiopental anesthesia". Their effect is exceeding that of the caffeine benzoate by several times [9]. This observation prompted more detailed studies of the antidepressant activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazines.

Objective. Assessment of antidepressant activity tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on the model of "behavioral despair" with the forced swimming by Porsolt.

Materials and methods. Four substances were selected from the group of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles (1-4), synthesized with by an uncatalyzed Mannich reaction [4, 8]. These substances showed the most effective  analeptic activity in previous studies on a model of "thiopental anesthesia".

Pharmacological studies were conducted on 36 adult albino rats weighing 230-270 g in autumn-winter period in an approved pharmaceutical laboratory SI "Lugansk State Medical University". The rats were divided into control group, the reference group (amitriptillin 5 mg / kg) and 4 experimental groups according to the number of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives in a similar dosage.

Stress state has been induced by the forced swimming, according to the generally accepted method [10]. The effect of the studied  tetrahydropyrido [2,1-b] [1,3,5] thiadiazines was estimated by the number of attempts to get rid of the situation and the duration of the animal activity.

Results and discussion. In the test of "behavioral despair", animals in the control group made a series of attempts of deliverance and then a stage of immobilization came. In that control group, the duration of activity was 1 minute 13 seconds. The reference group receiving the tricyclic antidepressant amitriptyline, attempted to get rid of the situation for a period exceeding 2.22 times the duration in the control group. Activity time exceeded by 3.88 times that observed in the control group. Laboratory rats receiving substances 2 and 3 shown an ability to increase the number of attempts to get rid of the situation and a longer time of activity. The number of attempts to get rid of the situation in these groups exceeded the number in the control group by 132.6% and 125.6%, respectively. Activity time for rats in the experimental group 2 exceeded the activity time of the control group by 117.1%.

        Conclusions. In the model of test "behavioral despair" with the forced swimming in albino rats,  the antidepressant activity of some compounds 3-R-8-Ar-6-oxo-3,4,7,8-tetrahydro-2H, 6H-pyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles was studied and compared to the activity of amitriptyline. For substance 2 (Ar = 4-MeOC6H4, R = cyclohexyl) and 3 (Ar = 3,4-(MeO)2C6H3, R = 2-Me-3-Cl-C6H3) the antidepressive effect considerably exceeded that of the reference drug. Further studies with analogs of such fused compounds are currently in progress.


  1. Krasnov V.N. Psihiatricheskie rasstroistva v obschemedicinskoi praktike [Psychiatric disorders in general medical practice] RMJ 2002;25:1187 – 1191 (in Russian)
  2. Ariyo A.A., Haan M., Tangen C.M. et al. Depressive symptoms and risk of coronary heart disease and mortality in elderly Americans/ Circulation 2000;102:1773.
  3. Larson S.L., Owens P.L., Ford D., Eaton W. Depressive disorder, dysthymia, and risk of stroke. Thirteen-year follow-up from the Baltimore Epidemiologic Catchment Area Study. Stroke 2001;9:1979.
  4. J.C. Bermello, R. P. Piñeiro, L.M. Fidalgo, H.R. Cabrera, M.S. Navarro. Thiadiazine Derivatives as Antiprotozoal New Drugs // The Open Medicinal Chemistry Journal, 2011, № 5, рр. 51-60.
  5. В.В. Доценко, К.А. Фролов, С.Г. Кривоколыско. Синтез частично гидрированных 1,3,5-тиадиазинов по реакции Манниха // Химия гетероциклических соединений 2015, Т. 51, № 2, с. 109–127. [Chem. Heterocycl. Compd. 2015, 51(2), 109–127].
  6. N. Shobana, P. Farid. 1,3,5-Oxadiazines and 1,3,5-Thiadiazines // In  Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. (Eds.); Elsevier: Oxford, 2008, vol. 9, pp. 457-521.
  7. H. Rodríguez, M. Suárez, F. Albericio. Thiadiazines, N,N-Heterocycles of Biological Relevance // Molecules 2012, 17, pp. 7612-7628; doi:10.3390/molecules17077612.
  8. Osolodkin Dmitry I. Inhibitors of Tick-Borne Flavivirus Reproduction from Structure-Based Virtual Screening / Dmitry I. Osolodkin, Liubov I. Kozlovskaya, Evgenia V. Dueva, Victor V. Dotsenko, Yulia V. Rogova, Konstantin A. Frolov, Sergey G. Krivokolysko, Ekaterina G. Romanova, Alexey S. Morozov, Galina G. Karganova, Vladimir A. Palyulin,Vladimir M. Pentkovski, Nikolay S. Zefirov // ACS Med. Chem. Lett. – 2013. – 4. –РР. 869−874.
  9. Bibik E. Yu., Yaroshevskaya O.G., Mischuk A.A., Frolov K.A., Docenko V.V., Krivokolisko S.G. /Izuchenie analepticheskoi aktivnosti proizvodnih tetragidropirido[2,1-b][1,3,5]tiadiazina // Tezisi nauchno_prakticheskoi konferencii «Himicheskie problemi sovremennosti» [Study of the analeptic activity of tetrahydropyrido [2,1-3] [1,3,5] thiadiazine derivatives // Abstracts of the scientific and practical conference "Chemical problems of the present"], Donetsk, 2016. – p. 104-106 (in Russian)
  10. Habriev G.U. Rukovodstvo po eksperimentalnomu doklinicheskomu izucheniyu novih farmakologicheskih veschestv [Manual on experimental preclinical study of new pharmacological substances], Medicine, Moscow. – 2005. – p. 832 (in Russian)
  • Open access
  • 76 Reads
Diversity of Bioactive Endophytic Streptomyces sp. Residing in a Common Weed, Parthenium hysterophorus (Asteraceae: Heliantheae)
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The sunflower family (Asteraceae) comprises of over 650 species making it the largest plant family in Pakistan. Members of this family are extremely diverse including weed plants such as Parthenium hysterophorus. The word endophyte means ‘in the plant’, the term includes the microbial colonizers which take up residence in the inner tissues of plants. Recently, Streptomyces species have been described in the plant tissues. It is noted that the possibility of re-isolation of compounds from soil actinomycetes has increased making it crucial that unexplored habitats be pursued for the search for new compounds. Considering this idea, we explored the diversity of endophytic Streptomyces residing in the common weed, Parthenium hysterophorus. A variety of Streptomyces sp. were identified through 16S gene sequencing that were not reported in prior studies to the best of our knowledge. The isolates were screened for their antimicrobial potential particularly against multidrug resistant (MDR) pathogens and for the diversity of their secondary metabolites through thin layer chromatography (TLC) and High performance liquid chromatography (HPLC-UV). The staining of the TLC plates by reagents such as Ehrlich’s reagent and anisaldehyde /H2SO4 revealed indoles and N-heterocycles whereas the HPLC-UV chromatograms revealed peaks of diverse compounds.

  • Open access
  • 79 Reads
A Short Peptide Inhibitor as an Activity-Based Probe for Matriptase-2
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Matriptase-2 is a type II transmembrane serine protease and the key regulator of systemic iron homeostasis. After its synthesis, matriptase-2 is present on the cell surface as an inactive zymogen which is activated by processing. Two processing steps lead to the release of a 55 kDa enzymatically active fragment of the protein into the cell culture supernatant. Since the underlying mechanism of these processing steps is not yet fully understood there is strong need for analytical tools that help to distinguish active and inactive matriptase-2. For this purpose, we present a short biotinylated peptide probe with a chloromethyl ketone group as an inhibitor and activity-based probe for matriptase-2. This probe was characterized in kinetic experiments and applied for in-gel detection of matriptase-2.

  • Open access
  • 74 Reads
Fragments of Peptoid 1:Synthesis of N-Substituted Glycine Monomers
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Peptoids are N-substituted glycine oligomers comprising multiple biomedical applications. In particular, they are used in nanotechnological approaches. In this context, their application is typically focused on larger oligomers, which form two-dimensional structures, but are difficult to be synthesized. However, a short peptoid of three N-substituted glycine building blocks, referred to as peptoid 1, is known to inhibit the proapoptotic protein APAF1. Herein, we report on the preparation of various peptoidic building blocks of peptoid 1. The synthesis was conducted by alkylation of two different amine components, 2-(2,4-dichlorophenyl)ethylamine and 3,3-diphenylpropylamine with tert-butyl bromoacetate, benzyl bromoacetate, and 2-bromoacetamide, respectively. The resulting glycine derivatives have been characterized by NMR and LC/MS data. The new peptoid units will be provided to biochemical studies, e.g. to the evaluation of protease-inhibiting properties, in order to perform a fragment-based approach.

  • Open access
  • 198 Reads
A Synthetic Entry to Amino Acid Derivatives through Davidson-like Heterocyclization
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The modification of amino acids leads to valuable building blocks for the synthesis of bioactive compounds. By keeping the amino group protected, the carboxylic acid functionality can be converted in two steps to an imidazole moiety via a Davidson-like heterocyclization. This reaction allows for a combinatorial approach, in which two positions at the heterocycle can be modified. Herein, we report on the synthesis of such imidazole derivatives by using N-protected cyclohexylalanine as the starting material, which was subjected to Davidson-like heterocyclization. By using different α-haloketones, two points of diversity were examined, position 4 and 5, respectively. The building blocks can serve as the starting point for the synthesis of bioactive peptides to be provided to pharmacological studies.