Administration of current non-steroidal anti-inflammatory drugs is often associated with serious adverse effects. Therefore, there is a constant need to develop new molecules with anti-inflammatory activity. On the other hand, thiourea derivatives of non-steroidal anti-inflammatory drugs demonstrated significant anti-inflammatory activity in numerous studies. To clarify anti-inflammatory mechanism of action, in silico study was performed on four thiourea derivatives of naproxen, which were selected from the initial group of compounds synthesized by our research group. Tested compounds contain p-fluoroaniline (16), p-methoxyaniline (17), p-ethoxyaniline (18) and aniline (19) in the side chains. Selected 3D structures of enzymes COX-2 (3NT1) and 5-LOX (6NCF) were taken from PDB database. MAKE Receptor 3.2.0.2 software was used for preparation of enzymes' active sites, while ligands were prepared in OMEGA 2.5.1.4. FRED 3.2.0.2 software was employed for the analysis of binding poses into enzymes' active sites. All tested compounds showed key binding interactions with both enzymes. The highest number of key binding interactions was observed during molecular fitting of derivative 19 into the active site of COX-2 and derivatives 16 and 18 into the 5-LOX. Derivative 17 had the lowest value of free binding energy for both target enzymes (-14.90 kcal/mol for COX-2 and -9.57 kcal/mol for 5-LOX). Therefore, all analyzed compounds represent potential dual inhibitors of mentioned enzymes.

During our research over biological activity of different N-aryl-4-substututed-pyridine-3-sulfonamides we have found that compound bearing N-(quinolin-8-yl) substituent possess a significant anti-tumor activity. Mechanisms of anticancer activity of N-(quinoline)sulfonamide derivatives was reported to be inhibition of NF-κB pathway. Nuclear factor NF-κB regulates expression of genes that control cell proliferation and cell survival thus it is consider as potential molecular targets for the prevention and treatment of cancer. Based on this information we decided to synthesize and evaluate series of 4-amino-N-(quinolin-8-yl)pyridine-3-sulfonamides, which contain both 8-amonoquinolin group and pyridine-3-sulfonamide scaffold.

Target compounds were obtained in multistep reaction starting from 4-hydroxypyridine, and their structure was confirmed using the spectroscopic methods: IR, ¹H NMR, and elemental analysis (C, H, N), Synthesized compounds were tested using MTT assay towards their effect on growth of three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa as well as on noncancerous keratinocyte cell line HaCaT. Cell viability was measured after 72 h of incubation with tested compound in five concentration 1 – 100 μM.

All compounds show very high activity comparable to cisplatin against cancer cells lines (IC₅₀=4-43 μM), and selectivity relative to HaCaT cells.

Our previous research proved that benzenesulfonylguanidine derivatives display significant cytotoxic activity against human cancer cells. Here, we describe new 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines with cytotoxic activity against HCT-116 and MCF-7 cells. The planned derivatives were obtained by a two-step synthesis. The starting substrates were 1-(2-alkylthio-4-chloro-5-methyl)benzenesulfonyl)-3-aminoguanidines 1-4 which were transformed into 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-[(2-chloroacetyl)amino]guanidines 5-8 by a reaction with chloroacetyl chloride. In the next step, the derivatives 5-8 were reacted with potassium thiocyanate yielding 1-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-3-(2-imino-4-oxothiazolidine-3-yl)guanidines 9-12.

The synthesized derivatives 5−12 were evaluated in vitro by MTT assays for their activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7, and cervical cancer HeLa. The activity against non-cancerous human epidermal keratinocyte line HaCaT was also examined. The data indicate that compounds 5-8 inhibit the growth of cancer cells stronger than derivatives 9-12. The selective cytotoxic effect against HCT-116 cells was found for benzenesulfonylguanidine 6 containing 2-(trifluoromethyl)benzylthio group at position 2 of benzenesulfonyl scaffold. The IC₅₀ value was 13 μM, while IC₅₀ for HaCaT cells was 48 μM. Good selectivity was also observed for compound 7, with 2-chloromethylbenzylthio substituent, against HCT-116 and MCF-7 cells (IC₅₀ = 12 and 19 μM, respectively for HCT-116 and MCF-7 cells, IC₅₀ = 47 μM for HaCaT cells). Among compounds 9-12, only compound 9 showed moderate but selective cytotoxicity against MCF-7 cells, with IC₅₀ = 18 μM compared with IC₅₀ = 54 μM for HaCaT cells.

Fenretinide (N-(4-hydroxyphenyl)-retinamide, 4-HPR) is a synthetic retinoid with fewer adverse effects than natural retinoids, effective against ovarian, prostate, small cell lung, brain, neuroectodermal-derived tumors. Clinical responses in adult and pediatric patients are often partial, revealing a limited activity of 4-HPR against existing disease. The underlying causes of this slight therapeutic efficacy consist in 4-HPR poor water solubility, low bioavailability and high first-pass hepatic effect. To overcome these drawbacks, nanomedicine could represent a valid alternative. We have already developed nanostructured drug delivery systems able to encapsulate 4-HPR. Indeed, polymeric micelles made of branched polyethylene glycol or amphiphilic dextrin have been prepared and investigated for their effectiveness both in vitro and in vivo. We have also designed a liposomal 4-HPR endowed with an active targeting moiety. Recently, we have focused our attention on a more physiological and not immunogenic drug delivery system. With this in mind 4-HPR-loaded mesenchymal stem cells-derived extracellular vesicles have been prepared. The drug amount encapsulated into the vesicles was determined by HPLC. Briefly, prior 4-HPR quantification an extraction procedure was optimized and, to estimate the analyte recovery an internal standard was employed. Since for this purpose, N-(4-ethoxyphenyl)-retinamide (4-EPR) has been reported, we developed a new operator-friendly one-step procedure to synthetize highly pure 4-EPR in quantitative yield. Studies aim to establish the best drug loading conditions are ongoing.

Diabetes Mellitus is one of the leading metabolic disorders which leads to chronic wounds of the lower limbs. Complications like abnormal vasculopathy and functioning of endothelial cells, decreased glucose-6-phosphate dehydrogenase, inadequate remodelling of extracellular matrix, decreased nitric oxide synthase, neuropathy, and secondary infections delay the process of wound healing which finally leads to amputation of the lower extremities. In-vitro and in-vivo studies exploring the role of the SIRT1 receptor in diabetic wounds have shown decreased expression of the receptor along with an increase in the levels of reactive oxygen species (ROS). Treatment with specific SIRT1 agonists in animal models has demonstrated an increase in angiogenesis and a faster rate of wound healing. Verbascoside has a potential role in wound healing by proliferation and keratinocyte migration, synthesis of extracellular matrix, increasing neutrophil and macrophage function, and increasing angiogenesis. Thus, a molecular docking study was conducted to evaluate the interaction between Verbascoside and the SIRT1 receptor (PDB ID: 4ZZJ). The least binding energy was found to be -9.6 kcal/mol which suggested a high binding interaction between the receptor and the ligand. The interacting amino acids include ARG274, GLU467, PRO468, LEU469, PRO470, PHE474, GLU477, ARG649, and VAL657 which is the common binding pocket for polyphenols. However, in-vitro and in-vivo studies are required to further evaluate the activity of Verbascoside in diabetic wound healing.

Prolonged production of inflammatory mediators derived from arachidonic acid through the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) is responsible for various inflammatory diseases. It was shown that inhibition of any of these pathways could potentiate the other one, so inhibition of both pathways represents a rational approach to the design and development of more effective and safer anti-inflammatory drugs. The aim of this study was synthesis, investigation of enzyme inhibition and redox properties of five N-hydroxyurea and hydroxamic acid derivatives (IND-NHU, FLU-NHU, DIKLO-NHU, IBU-Ac and NAP-Ac), designed as potential dual COX-2 and 5-LOX inhibitors, according to the structure-activity relationship (SAR) analysis of literature data. N-hydroxyurea analogs IND-NHU, FLU-NHU and DIKLO-NHU were synthesized in two steps reactions, while compounds IBU-Ac and NAP-Ac were synthesized in four steps reactions, according to previously published procedures. Effects of various concentrations of synthesized compounds were monitored on oxidative stress parameters (TOS, TAS, PAB and SHG) and calculated oxy scores (OS) had low values, which indicates good antioxidant potency. The ability of compounds to inhibit COX-2 and 5-LOX enzymes was determined using COX-2 and 5-LOX enzyme immunoassay kits. Derivatives FLU-NHU (IC₅₀ = 1.93 µmol), DIKLO-NHU (IC₅₀ = 0.91 µmol), IBU-Ac (IC₅₀ = 1.05 µmol) and NAP-Ac (IC₅₀ = 1.27 µmol) showed comparable 5-LOX inhibitory activity to commercially available 5-LOX inhibitor zileuton (IC₅₀ = 0.61 µmol). Derivative IND-NHU showed significant COX-2 inhibitory activity (IC₅₀ = 10 µmol), while investigation of COX-2 inhibitory activity of remaining compounds is in progress.

In previous studies, the thiourea derivatives of non-steroidal anti-inflammatory drugs demonstrated significant anti-inflammatory activity. In this pilot study, three thiourea derivatives of naproxen were selected from the initial group of synthesized compounds for evaluation of anti-inflammatory activity using carrageenan induced paw edema model of acute inflammation. Analyzed compounds contained ethyl ester of L-phenylalanine, p-methoxyaniline and p-ethoxyaniline in the side chains. Wistar albino male rats were divided into 9 test groups and 4 control groups. Test groups were treated with different oral doses of selected thiourea derivative of naproxen: 2.5 mg/kg, 5 mg/kg and 10 mg/kg body weight. Three control groups were treated with 2.5 mg/kg, 5 mg/kg and 10 mg/kg body weight of naproxen and one control group was treated with solvent 1% DMSO. The thickness of the left paw tissue of each rat was measured using a Digital Vernier caliper at the following time intervals: immediately before inducing inflammation and 1, 2, 3 and 4 hours after inflammation. All tested compounds in every tested dose in the fourth hour after carrageenan administration showed a statistically significant (p < 0.05) inhibitory effect on the increase of rat paw edema compared to control, except for L-phenylalanine ethyl ester derivative in dose of 5 mg/kg and p-ethoxyaniline derivative in dose of 2.5 mg/kg. The highest percentage of inhibition was exhibited by L-phenylalanine ethyl ester and p-methoxyaniline derivatives (10 mg/kg) in the last hour (81.81%). According to obtained results, L-phenylalanine ethyl ester derivative stood out for its dose- and time-dependent anti-inflammatory effect.

Aryl / heteroarylsulfonamides are an important group of compounds with different directions of biological activity. The number of literature reports on the antibacterial activity of sulfonamides is steadily increasing, bringing a lot of interesting data on the diverse structures and mechanisms of their pharmacological action. The presented research joins the stream of the search for new hybrid molecules being created as a result of the combination of various pharmacophores with interesting biological profiles. Particular attention was paid to their antibacterial activity. The new compounds were designed and obtained based on the structure of the pharmacophore group of 4-chlorobenzenesulfonamide functionalized in the 2-position on sulfur atom, and the structure of chalcone.

Taking into account the previous results of our own research and the available literature data, new N-(4-chloro-2-arylmethylthio-5-methylphenylsulfonyl)cinnamamide derivatives were designed and synthesized, which have pharmacophore groups in their structure, such as: 1-naphthylmethylthio and 6-chloropiperonylthio.

Preliminary microbiological analysis was performed using TLC-bioautography. The expected antibacterial activity of the obtained compounds was confirmed in in vitro tests against Gram-positive bacteria: S. aureus, S. epimermidis, E. hirae, E. faecalis and B. subtilis. In the next stage, the microbiological activity of selected compounds against clinical strains MRSA, CNS and MRSE was also tested. The derivatives' activity against bacterial biofilm and hemolytic activity on the peripheral blood of domestic sheep were also tested.

Apples are fruits of great agricultural and economic interest in Europe, being also highly appreciated for its nutritional value and its association with several health benefits. The largest amount of apple consumed in Spain corresponds to commercial and imported varieties, losing some autochthonous genotypes well adapted to our climate and geography. Some studies suggest that its consumption produces a decrease in the risk of suffering cardiovascular diseases and diabetes, which could be related to the presence of polyphenols.

The aim of this project is to evaluate the antioxidant, antidiabetic, and anti-obesity effects of pulp apple extracts through in vitro and in vivo assays. The fruits tested come from two commercial apple varieties, Pinova and Verde Doncella. The extraction of bioactive compounds was achieved by using methanol as solvent and ultrasonication.

Total quantity of polyphenols was determined using the Folin method. To determine the antioxidative properties, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay and the inhibition of xanthine oxidase were performed. To evaluate the antidiabetic and anti-obesity potential, we analyzed the production of advanced glycation end products and the inhibition of the enzymes α-glucosidase and pancreatic lipase. Additionally, Caenorhabditis elegans was used to assess the extracts toxicity and their abilities to interfere with the accumulation of lipid droplets.

The results of Verde Doncella are slightly better than Pinova variety. Verde Doncella shows better antioxidant, antidiabetic, and anti-obesity properties than the Pinova pulp extract, spite of having almost the same total polyphenol content.

Since its appearance in Wuhan on December 2019, finding ways to manage the COVID19 pandemic becomes the biggest challenge the world is facing. In this investigation, we used quantitative structure-activity relationship (QSAR) study, Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis and computational molecular docking simulations to screen and assess the efficacy of thirty-nine bioactive 9,10-dihydrophenanthrene analogues.

The density functional theory (DFT) calculations using B3LYP/6-31G(d, p) level was used for the calculations of molecular descriptors and the principal component analysis (PCA) was used to eliminated redundant and non-significant descriptors. After that, statistically robust models were developed using multiple linear regression (MLR) method. All derived models were then subjected to thorough external as well as internal statistical validations, Y-randomization and applicability domain analysis. These validations were carried out as per the OECD principles. The best built model is used to design new molecules that have good values of the inhibitory activity against SARS-CoV-2. Pharmacokinetics properties were then determined using ADMET analysis to weed out any that would be harmful to the human body or cause adverse effects. Through the use of computational molecular docking simulations, in silico research was conducted on deigned compounds to forecast their SARS-CoV-2 activity and determine the stability of the evaluated ligands during their contacts with the protein of desired activity.