Epstein–Barr virus (EBV) causes lymphocyte-proliferative diseases, such as Burkitt’s lymphoma, Hodgkin’s lymphoma, other B and T cell lymphomas. Recently the connection between EBV and autoimmunity diseases has been demonstrated. In recent years, several studies have explored the concept that the compounds that have anti-herpetic activity might be able to influence the cell cycle of infected cells, by eliminating them from the body. However, cell cycle regulation during EBV-infection and the effect of anti-EBV drugs have received only limited attention.

The aim of our work was to study derivatives of triazole (G14, G20, G22, and G24) as potential antiherpetic agent and their effect on the cell cycle of lymphoblastoid cell lines B95-8. According to PCR, anti-EBV activity was observed only for compounds G14 and G22, EC50 values were 27 and 100µg/ml. The В95-8 cells treated with all studied compounds were analyzed with the help of flow cytometry (cells were stained with propidium iodide). It was observed an induction of apoptosis in the presence of G22 at 700µg/ml; the proportion of apoptotic cells reached almost 40%. Other compounds G14 and G24 led to the switch of cells from the Sub G0 phase of the cell cycle to the G1 phase and subsequent activation of the S-phase. These compounds may play an important role as potential inducers of EBV lytic infection; with the addition of antiherpesvirus drugs, they could be therapeutically beneficial for EBV-associated tumors.

Imidazole occurs in most proteins as part of the side chain of histidine and constitutes a binding site for various transition metal ions in a large number of metalloproteins [1]. Consequently, the bonding between imidazole and transition metal ions is widely known [2] and of considerable interest especially in biological systems [3,4]. Consequently, copper(II)–imidazole systems with different ratios of imidazole to copper have been prepared and investigated by several researchers [5]. Moreover, being studied as models for copper proteins that contain both functionalities in the side chain [6], some mononuclear copper(II)–imidazole complexes with carboxylate ligands have been found to display a variety of pharmacological effects, including antitumor [7], superoxide dismutase and catecholase activities [8]. In order to contribute to the study of these systems, we have synthesized two new penta-coordinated copper(II) complexes with mixed-ligands, namely: imidazole and citric acid. The resulting compounds have shown remarkable antimicrobial and antifungal inhibition activities, which have been predicted by exploring the computational chemical reactivity of the two complexes [9].

References :

[1] J. Reedijk & E. Bouwman, Bioinorganic Catalysis, Marcel Dekker Inc., New York & Basel, 1999.

[2] K. D. Karlin & Z. Tyeklar, Bioinorganic Chemistry of Copper, Chapman & Hall, New York, 1993.

[3] E. Colacio, M. Ghazi, R. Kivekäs, M. Klinga, F. Lloret & J. M. Moreno, Inorg. Chem, 2000, 39(13), 2770–2776.

[4] M. T. Caudle, J. W. Kampf, M. L. Kirk, P. G. Rasmussen & V. L. Pecoraro, J. Am. Chem. Soc, 1997, 119(39), 9297–9298.

[5] (a) S. M. Morehouse, A. Polychronopoulou & G. J. B. Williams, Inorg. Chem, 1980, 19(12), 3558–3561. (b) G. Fransson & B. K. S. Lundberg, Acta Chem. Scand. A, 1974, 28(5), 578–588. (c) D. L. McFadden, A. T. McPhail, C. D. Garner & F. E. Mabbs, J. Chem. Soc., Dalton Trans, 1976, 47–52.

[6] H. Beinert, Coord. Chem. Rev, 1980, 33, 55.

[7] J. R. J. Sorrenson, Prog. Med. Chem, 1989, 26, 437. (and references therein).

[8] A. L. Abuhijleh & C. Woods, Inorg. Chim. Acta, 1993, 209, 187.

[9] Direm, A. Abdelbaky, M. S. M. Sayın, K. Cornia, A. Abosede, O. & García-Granda, S. (2018). Inorg. Chim. Acta. 478. 59–70.

Computational chemistry methods can significantly reduce experimental costs in early stages of a drug development project by filtering out unsuitable candidates and discovering new chemical matter. Molecular alignment is a key pre-requisite for 3D similarity evaluation between compounds and pharmacophore elucidation. Relying on the hypothesis that the variation in maximal achievable binding affinity for an optimized drug-like molecule is largely due to desolvation, we explore herein a novel small molecule 3D alignment strategy that exploits the partitioning of molecular hydrophobicity into atomic contributions in conjunction with information about the distribution of hydrogen-bond donor/acceptor groups in each compound. A brief description of the method, as implemented in the software package PharmScreen, is presented. The computational procedure is calibrated by using a dataset of 402 molecules pertaining to 14 distinct targets taken from the literature and validated against the CCDC AstraZeneca test set of 121 experimentally derived molecular overlays. The results confirm the suitability of MST based-hydrophobic parameters for generating molecular overlays with correct predictions obtained for 100%, 93%, and 55% of the molecules classified into easy, moderate and hard sets, respectively. The potential of this tool in a drug discovery campaign is then evaluated in a retrospective study with the aim to evaluate the correlations between activities and similarity score of a series of sigma-1 receptor ligands. The results confirm the suitability of the tool for Drug Discovery purposes finding the 67% of the most active ligands (≤10 nM) in Q1 of the ranking and the most active compound in position five.

Aims: Neurodegenerative disorders prevalence is growing due to life expectancy increase, thus the passage signs of time are clearly visible in the brain. Oxidative stress is a factor that contributes to the organic defenses imbalance, producing free radicals, brain-aging progression and various degenerative diseases. Macromolecules oxidative damage increases with age, leading to a progressive decline in cell and tissue function. Antioxidants reduce these free radicals formation or react with them by neutralizing them. Euterpe oleracea Martius, popularly known as açaí, is rich in α-tocopherol, fibers, lipids, polyphenols and mineral ions. Believes that polyphenols high content, among which flavonoids, confers to açaí fruits a variety of health promoting effects, including anti-inflammatory, immunomodulatory, antinociceptive and antioxidant properties. The present study aims to analyze, in silico, flavonoids physicochemical, pharmacokinetic and toxicological properties present in Euterpe oleracea Martius.

Place and Duration of Study: Pharmaceutical and Medicinal Chemistry Laboratory (PharMedChem) at Amapá Federal University (UNIFAP), Macapá, Brazil, between December 2017 and January 2018.

Methodology: Initially, selected 16 molecules present in Euterpe oleracea Martius, divided into açaí pulp and oil. The physicochemical properties of the flavonoids were analyzed by the rule of 5, pharmacokinetic properties in the QikProp module of the Schrödinger software and the toxicity profile using the DEREK program.

Results: Among physical-chemical properties, the flavonoid compounds catechin, epicatechin, luteolin, chrisoeriol, taxifolin, apigenin, dihydrocaempferol, isovitexin and vitexin presented good oral bioavailability. In pharmacokinetic properties, the molecules catechin, epicatechin, isovitexin, luteolin, chrisoeriol, taxifolina and isorhamnetina rutinosídeo presented the best results and high human oral absorption. In toxicological properties prediction the compounds presented good results, except for the isorhamnetina rutinoside and rutin compounds that presented alert about the mutagenicity for hydroxynaphthalene or derivative.

Conclusion: Catechin, chrysoerythol and taxifolin flavonoids presented the best results, but other computational and experimental methods are needed to identify these compounds biological activity.

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.