Third International Electronic Conference on Medicinal Chemistry (ECMC-3)

The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website (www.sciforum.net/conference/ecmc-3). Around 300 authors from 34 different countries participated at the event, which hosted more than 70 presentations, keynotes, videos, and posters. A short description of some works presented during that scientific meeting is disclosed in this report.

In recent years, the design of anticancer agents has received considerable attention in the field of medicinal inorganic chemistry. Zinc(II) ion plays an important role in bioinorganic processes because of the potential formation of coordination compounds in which zinc(II) ion can readily accommodate four-, five-, or six molecules. The advantage of zinc-based anticancer drugs could be their selectivity toward specific cellular targets thanks to specific coordination ability and kinetic properties (Bertini, I., et al. Inorg. Chem. 1990, 29, 1460-1463). their selectivity toward specific cellular targets thanks to specific coordination ability and kinetic properties (Bertini, I., et al. Inorg. Chem. 1990Chem. , 29, 1460Chem. -1463. The mole-ratio method was used for determining metal-ligand stoichiometry between [ZnCl2(en)] (where en = 1,2-diaminoethane or ethylenediamine) and imidazole at pH 7.2 in the presence of different chloride concentrations. The results indicated step-wise formation of 1:1 and 1:2 complexes in the presence of 0.010 M NaCl and 1:1 complexes in the presence of 0.001 M NaCl. Those results are correlated with additional coordination of chlorides in the first coordination sphere and with changes in coordination geometry. In the presence of 0.001 M NaCl, five-coordinate complex anion [ZnCl3(en)] − is formed initially, and then substitution reaction with imidazole occurred. In the presence of 0.010 M NaCl the octahedral complex anion [ZnCl4(en)] 2− formed.
The kinetics of ligand substitution reactions between complex and relevant nitrogen nucleophiles such as imidazole, 1,2,3-triazole and L-histidine were investigated at pH 7.2 as a function of nucleophile concentration in the presence of 0.001 M and 0.010 M NaCl. The reactions were followed under pseudo-first-order conditions by UV-vis spectrophotometry. The substitution reactions included two steps of consecutive displacement of chlorido ligands and changes in coordination geometry of [ZnCl2(en)] complex. Results are discussed in terms of mechanisms of interactions between potential antitumor zinc-based drugs and biomolecules.
* Correspondence: elodie.lohou@u-picardie.fr Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or malondialdehyde (MDA) are endogenously formed during the sugar glycoxidation and lipid peroxidation of polyunsaturated fatty acids induced by oxidative stress exacerbation. Their condensation with amino groups of tissue proteins gives Advanced Glycation Endproducts (AGE) and Advanced Lipid peroxidation Endproducts (ALE). In Alzheimer's disease (AD), extensive AGE/ALE accumulation has been reported in extracellular amyloid β (Aβ) plaques and intracellular tau-associated neurofibrillary tangles. Indeed, a critical imbalance between cerebral reactive oxygen species (ROS) production and endogenous antioxidant capacities associated with biometal dyshomeostasis has been suggested to be a driving force for AD onset and progression. Aβ-oligomers induce oxidative stress whereas transition metals (Zn 2+ , Cu 2+ and Fe 3+ ) stimulate Aβ aggregation and APP (amyloid precursor protein) processing. First, glycated Aβ cross-linking promotion accelerates its deposition and its protease resistance. Secondly, AGE/ALE formation not only accelerates tau hyperphosphorylation, disturbs the neuronal membrane depolarization process and the glucose transport but also exacerbates glutamate-mediated excitotoxicity. Thirdly, AGE promote via their receptors RAGE oxidative stress and inflammation as well as cell apoptosis.
Taking into account the multifactorial pathogenesis of AD, we designed new multifunctional drugs that are simultaneously able to trap RCS (primary vicinal diamine function) as well as ROS and biometals (phenolic acid or hydroxypyridinone moiety) ( Aim: To quantify the effect of one year r-GH therapy on blood gamma-amino-butyric acid(GABA), serotonin (5-HT), dopamine (DA) and IGF-1 in 15 growth hormone(GH) deficient children. Research design and methods: This retrospective study included 8 boys (7-14 years) and 7 girls (7-14 years) with clinically established GH deficit and under GH replacement therapy. In 2016 they were quantified for GABA, DA, 5-HT and IGF-1. After one year again of GH therapy they were once more tested for the same parameters using analytical methods. Results Median plasma parameters in 8 boys pre-vs. post-GH therapy was: GABA: 59.44 vs. 105.83 ng/mL; 5-HT: 269.66 vs. 196.55 ng/mL; DA: 46.66 vs. 91.5 pg/mL; IGF-1: 367.38 vs. 445.5 ng/mL. The same parameters were tested in 7 girls as median before and after GH therapy: GABA: 45 vs. 96 ng/mL, 5-HT: 215 vs. 200 ng/mL; DA: 40 vs. 60 pg/mL; IGF-1: 284 vs. 420 ng/mL. We established statistical significant differences in boys group before and after treatment in: plasma GABA (p < 0.001), serum 5-HT (p < 0.01), plasma DA (p < 0.02), serum IGF-1 (p = 0.02). In girls group we calculated statistical significant differences in plasma GABA before and after therapy (p < 0.001) and in plasma DA before and after therapy (p > 0.02). Conclusions: In fact replacement GH-therapy improved GABA/5-HT, GABA/DA, GABA/IGF-1, 5-HT/IGF-1 correlations in boys group. In girls group we estimated improved correlations between GABA/DA, 5-HT/DA, 5-HT/IGF-1. These observations could be translated in general improvement of health state in growth deficient children under GH-therapy. , by chiral LC analysis of their acidic hydrolysates, using appropriate D-and L-amino acid standards. The enantioseparations of the amino acids were successfully performed on a Chirobiotic T TM column under reversed-phase elution conditions. Actually, the teicoplanin selector of this column has several characteristic features that make it suitable for amino acid analysis (Berthod, A. et al. J. Chromatogr. A 1996, 731, 123-137). The elution order of all the standards amino acids enantiomers was confirmed by injecting solutions of the racemic or enantiomeric mixtures and then each enantiomer separately. The chiral LC technique was demonstrated to be decisive leading to the unambiguous elucidation of the amino acid constituents of the three bioactive marine natural products. 44, 1509-1524). In the present study, classification structure-activity relationship (C-SAR) models are developed to distinguish between high and low anti-HIV-1 inhibitors of these 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.
Acetylcholinesterase (AChE) is the enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into acetic acid and choline, a crucial mechanism for regulation of neurotransmission at synapses in all nervous systems. According to the cholinergic hypothesis, depleted levels of ACh are associated with Alzheimer's disease (Francis, P., et al. J. Neurol. Neurosurg. Psychiatry 1999, 66, 137-147).
As part of a program aimed at preparing new bioactive heterocycles with kinase and AChE inhibition properties, we designed and synthesized a series of (Z)-2-arylidene-and 2-aminomethylene derivatives of thiazolo[3,2-a]pyrimidine by a convenient multicomponent method. The products were fully characterized by 1D-and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which indicated a consistent Z-configuration at the arylidene and aminomethylene double bond. Additionally, molecular docking simulations of the series of 2arylidene/aminomethylene-thiazolo [ As part of a program aimed at preparing new bioactive heterocycles with kinase and AChE inhibition properties, we designed and synthesized a series of (Z)-2-arylidene-and 2-amino-methylene derivatives of thiazolo[3,2-a]pyrimidine by a convenient multicomponent method. The products were fully characterized by 1D-and 2D-NMR, high resolution ESI-MS/MS and single crystal X-ray diffraction analysis, which indicated a consistent Z-configuration at the arylidene and aminomethylene double bond. Additionally, molecular docking simulations of the series of 2-arylidene/aminomethylene-thiazolo[3,2-a]pyrimidine derivatives to human AChE (PDB ID: 4m0f, The design of novel and efficient compounds fighting against the highly variable RNA viruses, such as hepatitis C virus (HCV), is a major goal. Engineering different antiviral RNAs into a single molecule yields the so-called multivalent compounds, which are promising candidates for the development of new therapeutic strategies. In this work, the previously developed chimeric inhibitor RNA HH363-10 was used as archetype for the development of improved anti-HCV inhibitors. HH363-10 consists of a hammerhead ribozyme domain, targeting the essential internal ribosome entry site (IRES) region; and an aptamer RNA molecule, directed against the highly conserved IIIf domain of the IRES. Following to the application of an in vitro selection process, new multivalent optimized chimeric anti-HCV RNA molecules derived from HH363-10 were isolated. The aptamer RNA domain was evolved to contain two binding sites: the one mapping the IIIf domain, and a newly acquired targeting site, either to the IRES domain IV (which contains the translation start codon) or the essential linker region between the IRES domains I and II. These chimeric molecules efficiently and specifically interfered with HCV IRES-dependent translation in vitro (with IC50 values in the low μM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved, multivalent RNA molecules with potential clinical applications.  The design of novel and efficient compounds fighting against the highly variable RNA viruses, such as hepatitis C virus (HCV), is a major goal. Engineering different antiviral RNAs into a single molecule yields the so-called multivalent compounds, which are promising candidates for the development of new therapeutic strategies. In this work, the previously developed chimeric inhibitor RNA HH363-10 was used as archetype for the development of improved anti-HCV inhibitors. HH363-10 consists of a hammerhead ribozyme domain, targeting the essential internal ribosome entry site (IRES) region; and an aptamer RNA molecule, directed against the highly conserved IIIf domain of the IRES. Following to the application of an in vitro selection process, new multivalent optimized chimeric anti-HCV RNA molecules derived from HH363-10 were isolated. The aptamer RNA domain was evolved to contain two binding sites: the one mapping the IIIf domain, and a newly acquired targeting site, either to the IRES domain IV (which contains the translation start codon) or the essential linker region between the IRES domains I and II. These chimeric molecules efficiently and specifically Pharmaceuticals 2018, 11, 18 9 of 32 interfered with HCV IRES-dependent translation in vitro (with IC 50 values in the low µM range). They also inhibited both viral translation and replication in cell culture. These findings highlight the feasibility of using in vitro selection strategies for obtaining improved, multivalent RNA molecules with potential clinical applications.  In the present studies, we have found that the ORNs-D-M inhibit the upregulation of tlr3, tlr7, tlr8, nfkbia, nfnb1 nos2, xdh genes induced by influenza virus. By suppressing the upregulation of the nos2, xdh genes, the ORNs-D-M can decrease level of lipid peroxidation products at influenza virus infection in vivo. The ORNs-D-M modulate an up-expression of pro-oxidation and NF-kB signaling genes induced by influenza virus infection and are anti-influenza virus drug with effective anti-inflammation activity. By suppressing the expression of tlr3, tlr7, tlr8, the ORNs-D-M can impair the upregulation of nos2, xdh, nfkbia, nfkb1 induced by influenza virus. The ORNs-D-M can be antagonists of the Toll-like receptors 3, 7 and 8.   The aim of this work was to analyze the potential biological activity and the target of action of derivatives of polyfluorothioacylated amino acids by using in silico methods and examined received results by in vitro study. For this purpose, PASS software, web-server PharmMapper, PCR, MTT assay, trypan blue and neutral red assay were used. In the present study, PASS predicted that the The aim of this work was to analyze the potential biological activity and the target of action of derivatives of polyfluorothioacylated amino acids by using in silico methods and examined received results by in vitro study. For this purpose, PASS software, web-server PharmMapper, PCR, MTT assay, trypan blue and neutral red assay were used. In the present study, PASS predicted that the The aim of this work was to analyze the potential biological activity and the target of action of derivatives of polyfluorothioacylated amino acids by using in silico methods and examined received results by in vitro study. For this purpose, PASS software, web-server PharmMapper, PCR, MTT assay, trypan blue and neutral red assay were used. In the present study, PASS predicted that the The aim of this work was to analyze the potential biological activity and the target of action of derivatives of polyfluorothioacylated amino acids by using in silico methods and examined received results by in vitro study. For this purpose, PASS software, web-server PharmMapper, PCR, MTT assay, trypan blue and neutral red assay were used. In the present study, PASS predicted that the antiviral activity was expressed by the compound 10S20 and 10S21. According to PASS, all studied compounds may be a substrate for cytochrome c, that might play an important role in the induction of apoptosis. It was established, that majority of the targets are enzymes, such as protein kinases and apoptotic proteins. Any predicted property must be confirmed or disproved in the biological model. Accordingly, in vitro analysis of these compounds was carried out. Our results clearly show that all derivatives are quite toxic on model Raji and B95-8 cell line. Less toxic compound 10S20, at high concentration of 100 µg/mL exhibited a percentage of inhibition cell of 40%. Inhibition of 50 % of EBV replication was determined at minimum concentration of 1 µg/mL of compound 10S20. SI is used to estimate the therapeutic effect of a drug and to identify drug candidates for further studies. Thus, compound 10S20 could be considered as promising new anti-EBV drug candidate for infection of EBV. Obtained and analyzed data let to relate the compound 10S20 to a perspective anti-EBV agent, and the 10S21 and 10S22 derivatives to apoptosis-inducing compounds that can be used in further research on antitumor action. The study of know drugs and discovery of new compounds using not only standard mono-infections but also with created mixed infections is a topical and a new direction in antivirus screening. Previously in our department, the models of adeno-herpetic infections in cells of different origins were created and the features of the development of viral infections in these systems were studied

Study of Interactions between D-Mannitol and Polynucleotides
Volodymyr Shchodryi * and Zenoviy Tkachuk Institute of Molecular Biology and Genetics NASU, 150 Zabolotnogo Str., 03143 Kyiv, Ukraine * Correspondence: shodryj1992@gmail.com Complexes of oligoribonucleotides with D-mannitol are highly effective, non-toxic and with 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 does not have such biological effects.
During the research, we have observed the decrease of fluorescence intensity of the dye water solution with polyribonucleotides. 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 cases of polyguanilate and polyuridine minimum changes were observed. The spectral effect may indicate about more intense interaction between polyadenylate and polycytosine with D-mannitol. Also, we have recorded an increase in magnitude of the maximum absorption for polyadenylate and polycytosine during increasing the temperature. The value of the hyperchromic effect for polyadenylate is 10%, and 5% for polycytosine. Additional increase by the amount of hyperchromic effect was recorded for complexes with D-mannitol. Circular dichroism spectroscopy has shown spectra with a large difference in the structure of polyadenylate and polycytosine in compare with their complexes with D-mannitol. In case of polyguanilate and polyuridine and their complexes with D-mannitol, we have observed no changes in structure. Based on quantum-chemical calculations, it was established that two hydrogen bonds between D-mannitol and polynucleotides can be generated. The obtained data allow us to assume the presence of an additional D-mannitol helix in polynucleotide and D-mannitol complexes. This assumption was also confirmed by the simulation in program package Gaussian 09. The presence of the second helix can explain a wide range of actions of this complex of polynucleotides and D-mannitol against single and two-spiral viruses. . Our research has been related to the determination hepatoprotective activity of ORNs-D-mannitol during acute thioacetamide-induced hepatotoxicity. This study shows that ORNs-D-mannitol decrease lesions and inflammatory infiltration of liver parenchyma under thioacetamide-induced hepatotoxicity. The ORNs-D-mannitol attenuated thioacetamide-induced free radical damage of hepatic biopolymers that is expressed in reduction of TBA-reactive products, carbonyl derivatives and in recovery of protein thiol groups, reduced glutathione. In thioacetamide toxicity it was observed that the ORNs-D-mannitol reduced the expression mRNA level of proinflammatory (interleukin 6, tumor necrosis factor α) and profibrotic (collagen type I α1, α-smooth muscle actin, transforming growth factor β1) genes, that involved in the development of hepatotoxicity. Thus, the results of this work demonstrate that the ORNs-D-mannitol have hepatoprotective effects during acute liver injury.  Dec. 2009, 52, 583-590); TATE, a synthetic somatostatin analog, which binds specifically to somatostatin receptors present on the cell surface of neuroendocrine tumors (Bodei, L., et al. Eur. J. Nucl. Med. 2011, 38, 2125-2135); Substance P, peptide which has an important role in modulating pain transmission trough neurokinin type 1 (NK1r) and 2 receptors (NK2r), may play a role in the pathogenesis of pancreatic tumors and malignant glial brain tumors as well (De Araújo, E.B., et al. Cell. Mol. Biol. 2010, 56, 12). Different radiolabeling methods were assayed to establish the optimum conditions for obtaining the highest yield of labeled KCCYSL, TATE and substance P. Briefly, a stock solution of the three different peptides was prepared dissolving the peptides in Milli Q water (1 mmol/L each solution). After that, 20 µg of each peptide was added to three different Eppendorf tubes containing 0.2 mL ammonium acetate buffer (pH 4.8, 0.5 mol/L) and 10 MBq of 67GaCl3 (0.02 mL/0.1 mol/L HCl) was added to a reaction solution. The reaction mixtures were kept for 30 min at 80 • C. After cooling down, the preparations were studied by HPLC (C18 reversed phase column with gradient system was used with 0.1% trifluoroacetic acid/water (Solvent A) and acetonitrile (Solvent B) as mobile phase). The three peptides were successfully labeled with high yield (>99%) under optimized conditions and remained stable for more than 48 h at room temperature.

Acknowledgments:
The authors want to thank ANII, PEDECIBA-Quimica and PROINBIO for financial support.  2018, 11, 16). 5-Azacytdines are hydrolyzed at the cytosine's 6-position, but in vivo, the short half-life is governed by deamination. For decitabine, attempts have been made to address these issues with continuous infusion, but use of such a regimen is limited by inconvenience and toxicity.
A hydrophobic prodrug was developed for packaging in a hydrophobic matrix to protect NUC013 from hydrolysis and deamination. In an aqueous environment, the hydrophobic moieties are readily hydrolyzed with release of NUC013. This was achieved by conjugating NUC013 with trimethylsilyl (TMS) at the 3 and 5 position (NUC041).
The half-life of NUC013 administered IV in mice is 20.1 min. Below, PK following administration of a dose of 3 mg of NUC041 IM in a PEG-phospholipid-depot to mice: In an ongoing study, NUC041 was administered at a dose of 3 mg qwk to nude mice with NSCLC H-460 xenograft. After 3 days of treatment (n = 8), tumor starting volume had decreased by 4%. However, toxicity, likely from vehicle, was also observed at this dose. When non-small cell lung cancer tumors (NSCLC) in nude mice reached 32 to 75 mg mm 3 (day 4) treatment was initiated with gemcitabine (120 mg/kg IP q3dx9), NUC050 or NUC052 (both 40 mg/kg qwkx4) and compared to saline control (SC).
Gemcitabine inhibited tumor growth but was not tolerated. NUC050 resulted in inhibition to tumor growth on days 11-31 (p < 0.05), with a nadir of −73% compared to SC. Median survival was 25.5 days (SC) vs. 33 days (NUC050) ((hazard ratio) HR = 0.24, p = 0.017). NUC052 had the dose increased to 50 mg/kg after 2 doses. NUC052 resulted in inhibition to tumor growth on days 14-27 (p < 0.05), with a nadir of −45%, and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a NSCLC xenograft. The recent scope of pharmaceutical companies' R & D programs has been undergoing some changes, especially due to increased immunopharmacology-based treatments. A trend that has also been growing is the search for new activities that may be demonstrated by drugs already used in therapeutics. Herein, examples of antitumor small molecules lead compounds obtained in our research group that arise from two existing drugs, lucanthone (1) and mitoxantrone (2, MTX) are presented. The recent scope of pharmaceutical companies' R & D programs has been undergoing some changes, especially due to increased immunopharmacology-based treatments. A trend that has also been growing is the search for new activities that may be demonstrated by drugs already used in therapeutics. Herein, examples of antitumor small molecules lead compounds obtained in our research group that arise from two existing drugs, lucanthone (1) and mitoxantrone (2, MTX) are presented.

Old Pharmaceuticals with New Applications: The Case Studies of Lucanthone and Mitoxantrone
Lucanthone (1) was the antitumor model used to design inhibitors of P-glycoprotein with antitumor activity (Palmeira, A., et al. Biochem. Pharmacol. 2012, 83, 57-68) and activators of this transporter that could protect cells from xenobiotics were also unexpectedly discovered (Silva, R., et al. Arch. Toxicol. 2015, 89, 1783-800). Very recently, we engaged a project that intends to understand the Lucanthone (1) was the antitumor model used to design inhibitors of P-glycoprotein with antitumor activity (Palmeira, A., et al. Biochem. Pharmacol. 2012, 83, 57-68) and activators of this transporter that could protect cells from xenobiotics were also unexpectedly discovered (Silva, R., et al. Arch. Toxicol. 2015, 89, 1783-800). Very recently, we engaged a project that intends to understand the influence of metabolites in the cardiotoxicity of an antitumor drug, MTX (2). Studies on the cardio-toxicity of a synthetized metabolite, naphthoquinoxaline (NAPHT) revealed that the parent drug, MTX (2), caused a higher disruption in the energetic pathways in a cardiac model in vitro (Reis-Mendes, A., et al. Arch. Toxicol. 2016, 91, 1871-1890). Therefore, this metabolite could be regarded as a good option for a safer anticancer therapy since it is less cardiotoxic than MTX (2). Following, the synthesis of the major metabolites of MTX (2) was performed to proceed with further toxicological studies. The examples presented herein are expected to contribute to a recent trend in drug discovery, with the involvement of old pharmaceuticals in the drug discovery process.  The introduction of one or two acetoglycoside moieties in the framework of a hydroxylated flavonoid was performed using three synthetic methodologies: Michael reaction, Koenigs-Knorr reaction, and through a copper catalyzed azide-alkyne cycloaddition. Acetyl groups were introduced using acetic anhydride under microwave irradiation. The in vitro cell growth inhibitory activity of seven synthesized compounds were investigated in six human tumor cell lines: A375-C5 (malignant The introduction of one or two acetoglycoside moieties in the framework of a hydroxylated flavonoid was performed using three synthetic methodologies: Michael reaction, Koenigs-Knorr reaction, and through a copper catalyzed azide-alkyne cycloaddition. Acetyl groups were introduced using acetic anhydride under microwave irradiation. The in vitro cell growth inhibitory activity of seven synthesized compounds were investigated in six human tumor cell lines: A375-C5 (malignant melanoma IL-1 insensitive), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), U251 (glioblastoma astrocytoma), U373 (glioblastoma astrocytoma), and U87MG (glioblastoma astrocytoma). The most active compound in all tumor cell lines was a flavonoside and showed GI 50 values below 10 µM.

Synthesis and Tumor Cell Growth Inhibitory Effects of New Flavonosides and Xanthonosides
* Correspondence: o.neels@dkfz.de Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [ 18 F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [ 18 F]DCFPyL and [ 18 F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [ 18 F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, [ 18 F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [ 18 F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [ 18 F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.  The interesting 4H-chromenes (or 4H-benzopyranes) and their derivatives are components of many naturally occurring products, which have also been submitted to structural modifications to increase molecular diversity, for potential medicinal properties. In this context and starting from the 2-amino-2H-benzopyran-3-carbonitrile platform, it was possible to easily build (in 20 min) a new class of 4-imino-3-phenyl-3,4-dihydro-1H-chromeno [2,3-d] Rev. 2016, 329, 191-213).
N-acyclic carbenes are easily accessible via the reaction between isocyanide gold compounds and different amines. The reaction between one of those derivatives with different thiol groups, in presence of K2CO3 as a deprotonating agent, has led to a family of gold(I) NAC thioderivatives with N-acyclic carbenes are easily accessible via the reaction between isocyanide gold compounds and different amines. The reaction between one of those derivatives with different thiol groups, in presence of K 2 CO 3 as a deprotonating agent, has led to a family of gold(I) NAC thioderivatives with high cytotoxicity.
Biological activity of the different synthetized compounds was measured by MTT assays for different human cancer cell lines: A-549 (lung cancer), MiaPaca2 (pancreatic cancer), calculating their IC 50 values, which were found in many cases to be less than six, being these results very promising.  Rev. 2016, 329, 191-213).
N-acyclic carbenes are easily accessible via the reaction between isocyanide gold compounds and different amines. The reaction between one of those derivatives with different thiol groups, in presence of K2CO3 as a deprotonating agent, has led to a family of gold(I) NAC thioderivatives with high cytotoxicity.
Biological activity of the different synthetized compounds was measured by MTT assays for different human cancer cell lines: A-549 (lung cancer), MiaPaca2 (pancreatic cancer), calculating their IC50 values, which were found in many cases to be less than six, being these results very promising.  Chem. 2012, 20, 2923-2929). Interestingly, other thiourea derivatives such as thiazolidines have attracted great attention more recently because their biological activity (Liu, Y., et al. Bioorg. Med. Chem. 2011, 19, 2342-2348).
It is known that the coordination with different metals such as gold or silver could induce better biological activity (Rackham, O., et al. Biochem. Pharmacol. 2007, 74, 992-1002). Therefore, we decided to coordinate these metal centers to the thioureas and to the heterocyclic compounds synthesized by us.
Although the formation of thiazolidines by reaction of propargylamine with isothiocyanates under harsh conditions has been previously reported, the reaction between propargylamines and isothiocyanates (Scheme 1), when the stoichiometry was 2:1, is new and it showed the formation of pioneering thiourea-thiazolidine derivatives. These new molecules are able to coordinate metal centers through its sulfur and nitrogen atoms, improving their biological activity. On the other hand, these complexes could work recognizing different target cells leading to higher selectivity.
It is known that the coordination with different metals such as gold or silver could induce better biological activity (Rackham, O., et al. Biochem. Pharmacol. 2007, 74, 992-1002). Therefore, we decided to coordinate these metal centers to the thioureas and to the heterocyclic compounds synthesized by us.
Although the formation of thiazolidines by reaction of propargylamine with isothiocyanates under harsh conditions has been previously reported, the reaction between propargylamines and isothiocyanates (Scheme 1), when the stoichiometry was 2:1, is new and it showed the formation of pioneering thiourea-thiazolidine derivatives. These new molecules are able to coordinate metal centers through its sulfur and nitrogen atoms, improving their biological activity. On the other hand, these complexes could work recognizing different target cells leading to higher selectivity.
Finally, these compounds were tested with HeLa cells through the MTT assay. The results were not as successful as expected and only silver compounds showed good cytotoxic values as anticancer drugs. In contrast, gold compounds showed lower IC50 values than their respective organic ligands.

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Finally, these compounds were tested with HeLa cells through the MTT assay. The results were not as successful as expected and only silver compounds showed good cytotoxic values as anticancer drugs. In contrast, gold compounds showed lower IC 50 values than their respective organic ligands. Further studies will be performed to improve these activities and in order to develop better candidates for the treatment of cancer. The 1,4-dihydropyridine core is a widely studied privileged scaffold. Molecules containing this structure are well-known calcium channel blockers and are being used already as drugs in the treatment of heart diseases. Moreover, recent advances have demonstrated their potential to act against many other diseases. The recent research concerning their activity as multidrug-resistance reversing agents should be highlighted (Edraki, N., et al. Drug Discov. Today 2009, 14, 1058-1066). In the chemistry field, they are soft reducing agents and their chiral analogues have been used in asymmetric reductions with good results (Herrera, R. P. Top. Curr. Chem. 2016, 374, 29).

Organocatalytic Synthesis of Chiral 1,4-Dihydropyridines with Potential Biological Properties
As shown before, these molecules contain a chiral center in their C4 position. The control of the selectivity in chemical transformations has been a crucial challenge in organic chemistry. Nowadays, is well known that the living matter can actually discern between stereoisomers of the same compound. against many other diseases. The recent research concerning their activity as multidrug-resistance reversing agents should be highlighted (Edraki, N., et al. Drug Discov. Today 2009, 14, 1058-1066). In the chemistry field, they are soft reducing agents and their chiral analogues have been used in asymmetric reductions with good results (Herrera, R. P. Top. Curr. Chem. 2016, 374, 29).
As shown before, these molecules contain a chiral center in their C4 position. The control of the selectivity in chemical transformations has been a crucial challenge in organic chemistry. Nowadays, is well known that the living matter can actually discern between stereoisomers of the same compound. Nevertheless, there are scarce examples of procedures leading to enantiomerically enriched 1,4-DHPs, being most of them based on the use of chiral auxiliaries or chiral resolutions (Auria-Luna, F., et al. Adv. Synth. Catal. 2017, 359, 2161-2175). Finding new and more environmentalfriendly processes is also an interesting matter in chemistry, and organocatalytic procedures are a perfect tool to achieve this goal.
Herein, we report our recent advances in the development of new organocatalytic methodologies to produce enantiomerically enriched 1,4-DHPs (Auria-Luna, F., et al. J. Org. Chem. 2017, 82, 5516-5523). Interestingly, one of them, brings out another privileged scaffold, such as the oxindole motif (Auria-Luna, F., et al . Molecules 2015, 20, 15807-15826). Our methodologies could be perfect keystones leading to further research on the biological properties of these promising compounds. Adv. 2015, 5, 33450-33462). In view of the excellent emission properties of all tested compounds, a series of experiments were undertaken to test their cytotoxic activity and viability as specific cell imaging agents in human HeLa cervical cancer cells. Cytotoxicity studies performed revealed high activity for some of these novel structures, highlighting the importance of the fluorescent fragment in the efficiency of these promising anticancer agents (Fernández-Moreira, V., et al. RSC Adv. 2016, 6, 14171-14177).
Fluorescence cell microscopy pointed out the different biodistribution behavior depending on the fluorescent moiety, and both lysosomal and nuclear localization has been observed, which highlights and proposes the possibility for chiral and nonplanar bioprobes, as in the case of compound depicted in the figure, to exert a chiral recognition within the nucleus. Since the squaramide functionality provides a way to increase the transport ability of a receptor without significantly increasing the lipophilicity, it offers an ideal platform for designing future anion transporters. Further related studies with this research are ongoing in our lab and will be published in due course.

Optimization of Conditions for the Chromatographic Isolation of Isohexenyl Naphthazarin Derivatives from the Rhizome Callus of Echium Vulgare
Petar Stanić * and Nenad Vuković Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia * Correspondence: rope034@gmail.com Fluorescence cell microscopy pointed out the different biodistribution behavior depending on the fluorescent moiety, and both lysosomal and nuclear localization has been observed, which highlights and proposes the possibility for chiral and nonplanar bioprobes, as in the case of compound depicted in the figure, to exert a chiral recognition within the nucleus. Since the squaramide functionality provides a way to increase the transport ability of a receptor without significantly increasing the lipophilicity, it offers an ideal platform for designing future anion transporters. Further related studies with this research are ongoing in our lab and will be published in due course. Recently, naphthazarin derivatives have attracted huge attention due to their broad variety of biological activities, which include wound healing, anti-inflammatory effects, antitumor, anti-microbial and antithrombotic activity, etc. These compounds are not only important for their biological activity (and medicinal applications), but also in industry (food colorings, cosmetics, wood coatings, etc.). In this study, three naphthazarin derivatives (deoxyshikonin, acetylshikonin and β-hydroxylisovalerylshikonin) have been identified after isolation from the plant Echium vulgare, which is abundant in the Serbian territory as a wild and cultivated species. The plant itself has been characterized as having a low naphthazarin pigment content compared to Onosma visianii, Onosma paniculata, Alkanna tinctoria and Lithospermum erythrorhizon, which are used for mass production of these pigments. The isolation method described in this study makes possible preparation of a concentrated Echium vulgare extract. This concentrated extract can complement the plant extracts with higher naphthazarin pigment content that either are non-native or endangered in Europe. Recently, naphthazarin derivatives have attracted huge attention due to their broad variety of biological activities, which include wound healing, anti-inflammatory effects, antitumor, antimicrobial and antithrombotic activity, etc. These compounds are not only important for their biological activity (and medicinal applications), but also in industry (food colorings, cosmetics, wood coatings, etc.). In this study, three naphthazarin derivatives (deoxyshikonin, acetylshikonin and βhydroxylisovalerylshikonin) have been identified after isolation from the plant Echium vulgare, which is abundant in the Serbian territory as a wild and cultivated species. The plant itself has been characterized as having a low naphthazarin pigment content compared to Onosma visianii, Onosma paniculata, Alkanna tinctoria and Lithospermum erythrorhizon, which are used for mass production of these pigments. The isolation method described in this study makes possible preparation of a concentrated Echium vulgare extract. This concentrated extract can complement the plant extracts with higher naphthazarin pigment content that either are non-native or endangered in Europe.

Synthesis of Squaramides with Anti-tumor Activity
Juan V. In this study, the cytotoxic effects of different squaramides were tested against diverse cancer cells, such as HGC-27, HeLa, T98 and U87 cells, and non-cancer cells, such as EK293, MDCK and Vero cells. We found a disubstituted squaramide that showed an IC 50 of 1.8 µM against HGC-27 cells, which is considerably lower than the IC 50

Synthesis of Squaramides with Anti-tumor Activity
Juan V. Alegre-Requena 1 , Eugenia Marqués-López 1 , Raquel P. Herrera 1, *, Mireia Quintana 2 and Gemma Triola 2, * In this study, the cytotoxic effects of different squaramides were tested against diverse cancer cells, such as HGC-27, HeLa, T98 and U87 cells, and non-cancer cells, such as EK293, MDCK and Vero cells. We found a disubstituted squaramide that showed an IC50 of 1.8 μM against HGC-27 cells, which is considerably lower than the IC50 observed in the rest of the cell lines (Quintana, M., et al. Furthermore, the mechanism of action of this compound was evaluated. The results indicate that the decrease in cell viability produced by the squaramide is probably caused by G 0 /G 1 cell cycle arrest and caspase-mediated apoptosis. Additionally, the cell death produced by this compound is accompanied by autophagy induction having a protective effect and no signs of cathepsin-mediated cell death or necroptosis have been observed. The creation of compounds that trigger a specific cell death subroutine is preferred since it might avoid potential side-effects and nonspecific cytotoxic effects. Therefore, this squaramide and its derivatives could be promising molecules for the treatment of gastric carcinoma. parasitic disease in Latin America. The chemotherapy employed to control the parasitic infection is based on two drugs: nifurtimox (Nfx) and benznidazole (Bnz), requiring long-term treatment that can give rise to severe side effects. They are not active against all T. cruzi strains, exhibit low efficiency in long-term chronic infections, and are mutagenic. The search of new drugs is an urgent need (Cabrera M., et al. Toxicol. Lett. 2009, 190, 140).
In this work, we used three symmetrical diarylideneketones 1-3 containing thiophene and furan moieties. These molecules showed good to excellent trypanosomicidal activity and selectivity to the parasite, affected cruzipain, a proteolytic enzyme of the parasite, and the glycolytic enzyme, triosephosphate isomerase of T. cruzi (TcTIM) without affecting human´s TIM and showing effectiveness in protecting infected mice without toxic effects in vivo. Arylidene ketones 1 and 2 cause, after 24 h, late apoptosis/necrosis at a concentration of 20 times the value of its IC 50 (approximately 80% of late apoptosis/necrosis) like Nfx. What happens with compound 3 should be further studied since no death by apoptosis or necrosis is observed at a dose of 20 times the value of their IC 50 like Bnz  Antibiotic resistance is an emerging disease and a real problem of health. Resistance of Gram negative bacteria such as Acinetobacter baumannii and Escherichia coli to conventional antibiotics leads to therapeutic failure and requires new antibiotherapies. The use of the iron transport systems is one of the most promising strategies to overcome this resistance phenomenon. These specific routes of entry, essential for the survival of the microorganisms, allow ferric siderophore complexes to carry iron within the bacteria.
These systems allow the introduction of antibacterial agents (conjugates antibiotic-siderophore) or toxic complexes (gallium complexes) into the bacteria to kill them. Rhodotorulic acid (RA) is a siderophore transported by TonBox dependant Fhu receptors. These kinds of receptors are expressed by Acinetobacter baumannii and Escherichia coli. RA is dioxopiperazine iron chélater with hydroxamate as iron ligands and two asymmetric centers (S,S-configuration). This spatial orientation is essential for the Fhu receptors recognition. We have previously reported the asymmetric synthesis of 3-substituted 2-oxopiperazines. Herein, we present an original and a convergent strategy to synthesize RA and corresponding 3,6-disubstituted analogues. Siderophore-like test and measurement of the complexing strength of these compounds will be carried out. There is a clear unmet medical need in the field of infectious diseases. A major goal to fight resistant bacteria involves the design, discovery and development of new antibiotics particularly against multi-drug-resistant strains. Polymyxins, an old class of antimicrobial cyclic lipopeptides highly potent against therapeutically relevant Gram-negative bacteria, are now used as last resort antibiotics in hospitals because of their nephrotoxicity and neurotoxicity that require careful monitoring of the patient (Rabanal, F., et al. Nat. Prod. Rep. 2017, 34, 886-908). Our group has embarked in a project to design and develop new polymyxins devoid of toxicity problems using a versatile and chemically accessible scaffold structure (Rabanal, F., et al. Sci. Rep. 2015, 5, 10558). Compounds show a remarkable activity against Gram-negative bacteria. Herein, the last results of our recently designed polymyxin analogs are presented.
* Correspondence: niamh.oboyle@tcd.ie Estrogen receptor-α (ERα) is an important target for the design of drugs such as tamoxifen and fulvestrant. Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized-series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC 50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, a compound (1) featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, a phenoxybutyric acid derivative compound (2, below) was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 1 is a promising lead for development as a clinically relevant SERD, whilst compound 2 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
In particular, a compound (1) featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly, from series III, a phenoxybutyric acid derivative compound (2, below) was not antiproliferative and selectively downregulated ERβ. A docking study of the benzoxepin ligands was undertaken. Compound 1 is a promising lead for development as a clinically relevant SERD, whilst compound 2 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.
Diarylsulfonylureas (DSU) constitute a group of compounds which, unlike the N-alkyl sulfonylurea derivatives exhibit activity against a broad spectrum of syngeneic rodent solid tumors and human tumor xenografts. In our previous studies we have proved a significant potential of antitumor activity of 1-(4-substituted pyridine-3-sulfonyl)-3-phenylureas strongly affected by substituent at the position 4 of the pyridinesulfonamide scaffold (Szafrański K. Therefore, we have undertaken the synthesis (as presented on the scheme) of novel series of N-{[4-(1H-1,2,3-triazol-4-yl)methylamino/thio)pyridin-3-yl]sulfonyl}urea derivatives, and evaluation in MTT assay of their effects on the growth of human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa.

Conclusions
The third International Electronic Conference on Medicinal Chemistry was a successful event having gathered around 300 authors from 34 different countries (Austria, Belgium, Brazil, Bulgaria, China, Cuba, Ecuador, Egypt, Finland, France, Germany, Greece, India, Indonesia, Ireland, Japan, Latvia, Macedonia, Mexico, Morocco, Nigeria, Pakistan, Poland, Portugal, Romania, Russia, Serbia, South Africa, Spain, Switzerland, Ukraine, United Kingdom, United States of America, and Uruguay). The virtual exhibition hall hosted 20 media partners.
The award for the best presentation, as selected by the Scientific Advisory Committee, was given to the group of Jalal Soubhye (Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Campusplaine, CP 205/5, 1050 Brussels, Belgium) for their work entitled: "Dual Anti-Inflammatory and Anti-Bacterial Effects of Phenylhydrazide and Phenylhydrazone Derivatives".
Thanks to the support of the organizers, the sponsors, and the confidence of the participants, we are proud to announce that the fourth International Conference on Medicinal Chemistry will be held in November 2018 on www.sciforum.net/conference/ecmc-4. We hope that you will have the opportunity to attend, as authors or visitors.
Supplementary Materials: The full presentations are available online at www.sciforum.net/conference/ecmc-3.