Management of inflammation constitutes an unmet medical need because more people are afflicted with these conditions than any other disease state. Thus, there is a rising demand for safer and efficacious anti-inflammatories. Two pathways correlated to the arachidonic acid (ARA) cascade have been recognized, namely cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Emerging approaches for the treatment of inflammation have shifted towards simultaneously targeting multiple enzymes in the ARA cascade through combination therapy and multi-target inhibitors, to circumvent the risks associated with single enzyme or pathway inhibition. Pyridine nucleus represents an important scaffold in drug discovery due to its diversified biological activities. Based on these premises, it was rationalized to synthesize some pyridine/bipyridine carbonitrile derivatives and some related compounds, substituted or fused to other heterocyclic/aromatic rings, to be explored for their anti-inflammatory activity.

In vitro assay results revealed that 5 compounds showed significant COX-2 inhibitory potential with IC₅₀ values of 0.1 µM, compared to 0.049 µM for the reference celecoxib. 15-LOX inhibitory activities of the test compounds were also assessed (IC₅₀ values 2.09-7.21 µM, compared to 3.34 µM for the reference quercetin). Three compounds showed significant in vivo anti-inflammatory activity (higher % inhibition of edema than celecoxib). Moreover, histopathological examination revealed that they showed superior gastrointestinal safety profile (normal gastric mucosa with no ulceration). Some compounds reduced the expression levels of pro-inflammatory enzymes (COX-2 and iNOS) while increased that of anti-inflammatory cytokine (IL-10) in LPS-stimulated monocytes. They also restored TNF-α titer to the normal level of the control untreated cells. Docking of the most active compounds into COX-2 and 15-LOX active sites showed similar binding pattern to those of the cocrystallized ligands.

Nitro compounds show great importance in chemistry, biology and material sciences. Among them, nitropyridines and nitroanilines are widely used as useful intermediates for synthesis of biologically active compounds of pharmaceutical and agrochemical importance. Hence, we reported a powerful method for synthesis of various kinds of nitro compounds by using a three component ring transformation (TCRT) of dinitropyridone 1 with ketones in the presence of less nucleophilic ammonium acetate (NH₄OAc) as nitrogen source.

When pyridone 1 was reacted with aromatic ketone in the presence of ammonium acetate, 6-arylated 3-nitropyriines 2 were formed besides diazabicyclo compounds 3. This method was also applicable to cycloalkanones and α,β-unsaturated ketones to afford cycloalka[b]pyridines 4 and 6-alkynylated/alkenylated pyridines 5, respectively. It was found to be possible to use aldehydes as the substrate, what led to 3,5-disubstituted pyridines 6.

On the other hand, when aliphatic ketones were employed as the substrate, two kinds of ring transformation proceeded. Namely, 2,6-disubstituted 4-nitroanilines 8 were formed in addition to nitropyridines 7. This protocol was successful applied to synthesis of N,N,2,6-tetrasubstituted nitroanilines 9 upon treatment of dinitropyridone 1 with ketone and amine in the presence of acetic acid.

The racemic synthesis in four steps of pyrazole SKF-96365 analogues without substituent (CF₃ group) on the pyrazole platform was realized in moderate to good yields. The separation of (±) hydroxyl enantiomers 4 was developed successfully using the method of "half-concentration" with commercial (+)-(1S)- and (-)-(1R)-10-camphorsulfonic acid (CSA) followed by neutralization of diastereomers with MeONa in dry MeOH solution. With the pure enantiomers (-)-(1S)-4b and (+)-(1R)-4b, initial attempts to obtain the crystallized (-)-(1S)-7d and (+)-(1R)-7d after treatment of intermediate 6d with a solution of 1M HCl (for precipitation of hydrochloride salt 7d) failed. We have also investigated the effects of compounds 7(a-d) on endoplasmic reticulum (ER) Ca²⁺ and SOCE on PLP-B lymphocyte cell line and compound 7d was identified as a better SOCE inhibitor than SKF-96365. This preliminary SAR study showed that the MeO group in para-position of the phenethyl-1H-pyrazolium skeleton or for the Cbeta-phenylpropoxy side chain of 7 influenced the SOCE activity.

Cancer is one of the leading causes of mortality across the globe and is a growing public health issue. Existing agents used in treatment of cancer are known for serious undesirable effects. Hence there is urgent need for new anticancer drugs. In the present work, molecular docking analyses of a few chalcones into the ligand binding domain of epidermal growth factor receptor is reported. The 3D structures of all the 15 designed chalcone derivatives were sketched using chemsketch and geometric optimization with 1000 iterations was carried out using universal force field in Argus Lab until each ligand converged to lowest energy state and saved in .pdb format for docking process. Receptor (Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor Erlotinib) Pdb-id: 1M17 was undertaken for the analyses. Molecular modeling and docking approaches have been implemented to compare the binding efficiency of the indigenous inhibitor Erlotinib and the designed 15 chalcone derivatives with EGFR kinase.

There has been a persistent effort to improve efficacy of conventional antimycotic drugs. However, current antimycotic interventions have often limited efficiency in treating fungal pathogens, especially those resistant to drugs. Considering development of entirely new antimycotic drugs is a capital-intensive and time-consuming process, we investigated an alternative approach termed drug repurposing whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antimycotic agents. As a proof of concept, we applied chemosensitization as a new screening strategy, where combined application of a second compound, viz., chemosensitizer, with a conventional drug could enhance antifungal efficacy of the drug co-applied. Unlike the conventional combination therapy, a chemosensitizer itself does not necessarily have to possess an antifungal activity, but the chemosensitizer significantly debilitates defense systems of pathogens to drugs, enabling improved identification of antifungal activity of off-patent drugs. Of note, inclusion of fungal mutants, such as antioxidant mutants, could facilitate drug repurposing process by enhancing the sensitivity of antifungal screening. Altogether, our strategy could lead to high efficiency drug repurposing, which enhances the drug susceptibility of targeted fungal pathogens.

The natural-like spiroketal, 2-hydroxy-8-methyl-1,7-dioxaspiro[5.5]undec-3-en-5-one (1) has been synthesised and has shown a potent antitumor activity against human tumor cells of different nature and histotype. We have now performed studies to verify its in vivo activity on a murine melanoma model and in vitro studies to shed some light on the mechanism of action. Spiroketal 1 have shown a potent dose-dependent antitumor efficacy in vivo in a syngenic murine model (C57Black mice) of melanoma (B16). The compound suppressed the tumor growth by an average of 90% at a dose of 5 mg/kg by intra-peritoneum administration at alternate days for 15 days. It also displayed high antitumor activity in vitro in the B16 cells with nanomolar IC₅₀ value. In addition to the proapoptotic and telomerase inhibition activities, compound 1 has shown to inhibit cell migration and to strongly reduce the HIF1alfa expression, that is considered a regulator of multiple cellular functions related to the progression from primary to metastatic cancer disease. Therefore, although the full mechanism of action of this molecule has yet to be completely elucidated, spiroketal 1 is a promising antitumor drug candidate for the clinical treatment of melanoma and various cancers.

References: Fuggetta, M. P.; De Mico, A.; Cottarelli, A.; Morelli, F.; Zonfrillo, M.; Ulgheri, F.; Peluso, P.; Mannu, A.; Deligia, F.; Marchetti, M.; Roviello, G.; Reyes Romero, A.; Dömling, A.; Spanu, P. Synthesis and Enantiomeric Separation of a Novel Spiroketal Derivative: A Potent Human Telomerase Inhibitor with High in Vitro Anticancer Activity. J. Med. Chem. 2016, 59, 9140−9149 and references quoted therein

Reactive carbonyl species (RCS) are now considered to play an important role in Alzheimer's disease (AD) pathogenesis. Indeed, 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 leads to AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts) accumulation in amyloid β (Aβ) plaques and tau-associated neurofibrillary tangles (NFT). In AD, Aβ-oligomers induce oxidative stress whereas transition metals (Zn²⁺, Cu²⁺ and Fe³⁺) stimulate Aβ aggregation and APP (amyloid precursor protein) processing. Carbonyl stress takes part in this vicious downward redox amyloid spiral leading to neurodegeneration as oxidative stress promoter and toxic mediator.^1,2 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 oxidative stress and inflammation as well as cell apoptosis via their receptors RAGE.³
Taking into account the multifactorial pathogenesis of AD, we developed promising hybrid drugs that are simultaneously able to trap RCS (primary vicinal diamine function) as well as ROS and biometals (phenolic acid or hydroxypyridinone moiety).⁴ In the poster, synthesis of these new multifunctional AGE/ALE inhibitors and their physicochemical and biological evaluations (carbonyl trapping capacity, antioxidant activity, Cu²⁺-chelating capacity and protective properties against in vitro MGO-induced apoptosis in the model AD cell-line PC12) are reported.

We thank “SATT Nord” for financial support of this study.
References
1. D.A. Butterfield, J. Drake, C. Pocernich and A. Castegna, Trends Mol. Med., 2001, 7, 548-554.
2. A. Tiiman, P. Palumaa and V. Tougu, Neurochem. Int., 2013, 62, 367-378.
3. M. Krautwald and G. Münch, Exp. Gerontol., 2010, 45, 744-751.
4. E. Lohou, N.A. Sasaki, A. Boullier and P. Sonnet, Eur. J. Med. Chem., 2016, 122, 702-722.

CLL (Chronic Lymphocytic Leukaemia) is the most common leukaemia in the Western world. Classed as a clonal disorder of mature B-lymphocytes, CLL patient prognoses are broadly subdivided by the mutational status of the Immunoglobulin G Heavy Chain Variable region (IGHV) (with unmutated IGHV holding a better patient prognosis than the wild type variant)¹.

Structures related to tricyclic and tetracyclic anti-depressants (fluoxetine,maprotiline respectively) have previously been shown to exert potent, selective antiproliferative and pro-apoptotic effects in vitro and were met with marked success in related B cell malignancy cell lines, namely Burkitt’s Lymphoma (BL) cell lines DG-75 and MUTU-1².

Based on these preliminary studies, libraries of structurally related novel ethanoanthracene compounds were designed, based on the proven effectiveness of nitrostyrene core moiety derivatives and literature evidence of selective toxicity of chalcone moieties in leukaemic cell lines³.

The antiproliferative activity of each compound was determined using Alamar Blue assays on the two types of CLL cell lines: HG-3 and PGA-1, representative of bad and good prognosis respectively. The most promising activity was observed with maleimide dienophile based ethanoanthracene chalcones, particularly at a 10 µM across both cell lines. A ROS (reactive oxygen species) dependant activity was noted as both nitrostyrene and chalcone based analog biological activity markedly decreased on addition of NAC (N- acetyl cysteine) or Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).

References

1. Scarfò, L.; Ferreri, A. J. M.; Ghia, P., Critical Reviews in Oncology/Hematology, 2016, 104, 169-182.
2. Mc Namara, Y. M., Bright, S.A., Byrne, A.J., Williams, D.C., Meegan, M.J., European Journal of Medicinal Chemistry 2014, 71, 333.
3. Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z., Chemical Reviews, 2017, 117(12):7762-7810.

Aim: Hepatic fibrosis is a common consequence of chronic liver injury caused by a variety of etiological factors. It is associated with inflammation, oxidative stress, necrosis and ends with cirrhosis, liver cancer, or liver failure. Oligoribonucleotides-D-mannitol complexes (ORNs-D-M) display a vast spectrum of biological effects, including cellular metabolism stimulation with activation of endogenous synthesis of regulatory proteins, stimulation of reparation processes. Therefore, the aim of this study was to investigate the protective effect of the ORNs-D-M on liver fibrosis.

Materials and methods: Mice received thioacetamide (TAA) (200 mg/kg, intraperitoneal) thrice weekly, for 8 successive weeks to induce liver fibrosis. The ОRNs-D-M (200 mg/kg, per os) was administered orally during TAA intoxication. Body weights and mortality mice were assessed during the experiment. At the end of the experiment, oxidative stress, inflammatory and profibrogenic markers were evaluated.

Results: The results of the research showed that treatment with the ORNs-D-M attenuated TAA-induced liver fibrosis in mice. The ORNs-D-M prevented TAA oxidative stress. The ORNs-D-M decreased TBA-reactive substances, carbonyl derivatives levels and myeloperoxidase activity by 60.6, 35 and 52% respectively in comparison to control thioacetamide in the liver cells. In addition, these complexes increased protein and non-protein thiol groups levels, and glutathione-S-transferase and glutathione peroxidase activities compared to the TAA-treated mice. During TAA-induced liver fibrosis, it was investigated that the ORNs-D-M reduced the expression mRNA level of pro-inflammatory (IL-6, TNF-α) genes by 40 and 56 % respectively, compared to the mice with TAA. Furthermore, the ORNs-D-M suppressed the HSCs/myofibroblasts activation by reduced expression of markers α-SMA, COL-1, and TGF-β1 in the liver.

Conclusion: The ORNs-D-M could ameliorate the effects of TAA-induced liver fibrosis in mice by inhibiting oxidative stress, expressions of pro-inflammatory cytokines and profibrotic markers.

Ever since their discovery, hydantoins have attracted huge attention due to their intriguing properties, vast chemical diversity and potential, as well as their broad spectra of biological activity. The wide set of their biological activity includes antimicrobial, antitumor, antiandrogen, anticonvulsant, antiteratogenic activity, etc. They are also used in the treatment of cachexia, psoriasis, wounds in general and also as muscle relaxants.

There are many synthetic routes to hydantoins and some of them involve amino acids. As rigorous chemical conditions are not required, these reactions can be manifested in physiological conditions too, especially in the cases when protein consumption is increased and thus hydantoins have been isolated from urine. With all this in mind, elucidation of biological implications of hydantoins gains importance.

In this study, an amino acid derived 2-thiohydantoin, 5-​[2-​(methylthio)​ethyl]​-​3-​(2-​propen-​1-​yl)​-​2-​thioxo-4-​imidazolidinone, has been synthesized and fully characterized by NMR and IR spectroscopy, as well as X-ray crystallography. An extensive antimicrobial study has been carried out on ten bacterial isolates (Gram-positive and Gram-negative), as well as on five fungal isolates. Cytotoxicity has been tested on the cell lines of the normal lung fibroblasts, as well as breast, colon and lung tumor cell lines. Ultimately, a fish embryo toxicity (FET) assay has been carried out in vivo on the zebrafish model, testing for lethal and teratogenic effects and cardiotoxicity. Based on the found biological activity in previously mentioned assays, a determination of therapeutic potential has been carried out to show whether the compound is toxic in antimicrobial and anticancer doses.