Neurodegenerative diseases are the seventh death cause worldwide, being Alzheimer’s disease the most common. Serum albumin is the main multifunction protein in the blood stream, taking care of the clearance of products from cell metabolism or abnormal machinery. One of them is A beta peptide, involved in the formation of amyloid fibrils, one of the main hallmarks of Alzheimer’s disease. Hence, serum-albumin based therapies may offer an important potential to fight against this disease. Also, small metal nanoparticles with negative surface charge showed an efficient dissembling of preformed amyloid fibrils, so the combination of both components shows a great potential for a possible therapeutic nanoplatform. In the present work we synthesized and characterized small gold nanoclusters embedded in bovine serum albumin by an in-situ synthesis process. Gold metal nanoclusters have unique optical properties due to their small size. They have molecular-like electronic states that produce a large Stokes shift fluorescence phenomenon. Fluorescence Spectroscopy and HRTEM measurements assessed the correct formation of the metal nanoclusters inside the protein. The colloidal stability of the metal cluster-protein complexes was evaluated under different solution conditions (ionic strength and pH for 7 days). The biocompatibility of the nanoclusters-protein complexes was assessed in vitro in different cell lines by means of the CCK-8 viability assay. Finally, the effect of the nanoclusters in the fibrillation process of serum albumin taken as a model fibrillating protein was evaluated to decipher the therapeutical potential of such complexes for intended Alzheimer’s treatment in the future.

Medication non-adherence poses considerable challenges in managing chronic diseases and is associated with almost 200,000 deaths and €80-125 billion of potentially preventable direct (e.g. hospitalizations, waste of medication) and indirect (e.g. work productivity losses) costs in the European Union alone. The increasing awareness of the contribution of the acceptability of drug products by the patient to medication adherence and clinical outcomes is driving the integration of Patient Centric drug Product Design (PCDPD) into the pharmaceutical development process.

Regulatory agencies have addressed the relevancy of placing the patient in the center of pharmaceutical development. EMA has issued guideline/reflection papers for pediatric and older populations while FDA has developed a series of guidance documents on patient focused drug development with the primary goal to better incorporate the patient’s voice in drug development and evaluation.

PCDPD can be defined as the process of identifying the comprehensive needs of the target patient population to support the design of drug products. Three major factors are analyzed in PCDPD, namely patient, drug and drug product characteristics. This systematic approach integrates this insight which is translated to a Target Product Profile (TPP) to drive the pharmaceutical product design process.

Two case studies will be presented focused on the pediatric population and on patients with a chronic skin disorder (psoriasis) which will highlight the roadmap for a successful PCDPD.

The increasing morbidity and mortality caused by infections with pathogenic bacteria (fungus or bacteria) have highlighted an urgent requirement for developing novel anti-bacterial agents to protect the health and integrity of human life.18β-glycyrrhetinic acid has a wide range of pharmacological effects including anti-bacterial, anti-inflammatory and anti-tumor. Nevertheless, its relatively low biological activity and high toxicity limit its potential for anti-bacterial and other pharmaceutical applications. To improve the anti-bacterial activity of 18β-glycyrrhetinic acid, we designed and synthesized a total of 21 glycyrrhizic acid derivatives in 40-82% yields, among which 18 novel glycyrrhetinic acid derivatives, and the anti-bacterial and anti-fungal activities of all synthesized derivatives were evaluated in vitro by measuring the minimum inhibitory concentration (MIC) of the compounds against the strain. The evaluation results showed that most of the compounds showed good inhibitory activity against different strains, among which compound 1(MIC: 2 μg/mL)and compound 3 (MIC: 2 μg/mL)showed the strongest anti-fungal activity against Cryptococcus; Compound 20(MIC: 4 μg/mL) showed high anti-bacterial activity against Pseudomonas aeruginosa and merits further exploration as a new anti-bacterial and anti-fungal agent.

Silver nanoparticles (AgNP) have gained access to our daily life, resulting in exponential and inevitable human exposure, namely by the oral route. Despite this, the adverse effects of AgNP on intestinal cells are still unexplored. Thus, this study aimed to investigate the potentially toxic and pro-inflammatory effects of polyvinylpyrrolidone (PVP)-coated AgNP (5 and 50 nm) in intestinal epithelial C2BBe1 cells. For this purpose, the effects of PVP-AgNP in cellular metabolic activity and viability, and also in the expression levels of inducible nitric oxide synthase and iкBα were evaluated. It was observed a decrease of cellular metabolic activity, associated with the occurrence of early and late apoptotic events, for the 50 nm PVP-AgNP. The expression levels of inducible nitric oxide synthase and iкBα levels increased and decreased, respectively, after exposure to 50 nm PVP-AgNP. Ultimately, it was also observed an increase in nitric oxide levels. Therefore, it can be concluded that the larger PVP-AgNP induce prominent activation of a putative inflammatory response by intestinal cells. However, further studies are needed to disclose the mechanistic pathways involved in intestinal pro-inflammatory effects of AgNP.

In the Bidiuam, PubMed, SciHub, Elvesier, Academic Search Complete, Google Scholar and CAS-SciFinder databases, information reported on porphyrin-type compounds with anticancer and bactericidal activity was sought, to analyze it and obtain the molecular descriptors using the free ChemDes web platform. The calculated descriptors belong to the subprograms: PaDel, BlueDesc, RDkit and Pybel. The Build QSAR program was used to build and analyze QSAR models containing from one to six descriptors. Data were analyzed with cell lines HCT-116, HeLa, MCF-7 and MDA-MB-231, as well as with reported biological activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa bacteria. An evaluation of the model was carried out through internal cross-validation with the Leave-One-Out (LOO) method, with a Q² > 0.5 and that the difference of R²-Q² was ≤ 0.3. QSAR models with R² close to 1 and Q² > 0.5 were obtained; mainly on HeLa and HCT-116 cell lines, as well as models for bactericidal activity against E. coli and P. aeruginosa were obtained. From these models, 20 new porphyrin derivatives were designed, both with a pyrrole core and using their furan and thiophene bioisosteres. For each model, these compounds were predicted to have very good anticancer and bactericidal activity. Therefore, the synthesis of these compounds is being carried out to evaluate their biological activity.

Physiological and pathological functions of thioredoxine reductase (TrxR) system in cellular processes have been extensively investigated. Available evidences approve that dysregulation of TrxR results in various human diseases, especially cancer.

An increasing number of TrxR inhibitors which are in clinical trials for the treatment of different types of cancers has been reported so far. However, construction of the specific inhibitors of TrxR over other related enzymes (e.g. glutathione reductase) remains a challenge.

One of our research direction, is synthesis of small, structurally diverse products to define a new and selective class of Trx inhibitors. Herein, we present a library of natural small compounds (including sanatmarine, coumarine and asparagusic acid derivatives) possessing a potential Michael acceptor moiety and disulfide bond, respectively. The preliminary biological activity results proved the obtained library to be specific inhibitors although the mechanism of action and stability is still under investigation.

More recently scientific attention is paid on non-platinum based drug especially on bio-essential metal ions. Design of the heterometallic complexes is possible way to overcome limitation of platinum-based drugs.
The four novel complexes [{cis-PtCl(NH3)(μ-4,4′-bipyridyl)ZnCl(terpy)}](ClO4)2, [{trans-PtCl(NH3)(μ-4,4′-bipyridyl)ZnCl(terpy)}](ClO4)2, [{cis-PtCl(NH3)(μ-pyrazine)ZnCl(terpy)}](ClO4)2 and [{trans-PtCl(NH3)(μ-pyrazine)ZnCl(terpy)}](ClO4)2 (where terpy = 2,2′:6′,2′′-terpyridine) were synthesized and characterized. The binding of the heterometallic bridged cis-or trans-Pt(II)-Zn(II) complexes to calf thymus DNA (CT-DNA) was studied using UV absorption and fluorescence emission spectroscopy. The results indicate that the complexes bind strongly to DNA (Kb, in the order of 104 M−1) through groove binding, hydrogen bonds, and hydrophobic or electrostatic interaction. According to Stern–Volmer quenching constant (KSV) and binding constant (K), the [{cis-PtCl(NH3)(μ-4,4′-bipyridyl)ZnCl(terpy)}](ClO4)2 complex interacts with CT-DNA-EB more strongly than the rest of the studied complexes.

Skin aging is a progressive biological process of the human body that depends, among several phenomena, on degradation of proteins of extracellular matrix as well as the appearance of hyperpigmented spots. In previous studies, we demonstrated that differently substituted 3-arylcoumarins efficiently inhibit skin aging-related enzymes, such as tyrosinase, elastase and collagenase. According to these considerations, we have modulated this scaffold to improve the inhibitory potency against tyrosinase, elastase and collagenase, extending the study to the inhibition another enzyme, hyaluronidase. Moreover, photo-protective effect of the compounds has been also evaluated by determining the Sun Protection Factor. Starting from 3-(3’-hydroxyphenyl)-6,7-dihydroxycoumarin and 3-(2’-hydroxyphenyl)-6,7-dihydroxycoumarin, that overall revealed to possess the best inhibitory effects against skin aging-related enzymes, we selected for this study new molecules including bromine atoms together with the previously studied hydroxyl groups. Some compounds present multitarget properties towards the selected enzymes, along with a good photo-protective effect. These data support our previous findings on 3-arylcoumarin as promising scaffolds for the design of skin anti-aging agents.

Quinolinequinones, which are bicyclic heterocycles and quinone derivatives and due to their broad range of biological activities, which include strong antifungal, antibacterial, antimalarial, and anticancer, have long been the subject of numerous investigations. After successful synthesis and characterization of aminated quinolinequinones (AQQ) and antimicrobial evaluation by our group, compounds were subjected to NCI-60 Human Tumor Cell Lines Screen to determine anticancer activity. According to the NCI report, we further investigated the cytotoxic effects of selected compounds, AAQ6 and AAQ9, on the growth of DU-145 prostate cancer, MDA-MB-231 breast cancer, HCT-116 colon cancer line after 24-hour treatment by MTT assay at 1-100 μM concentrations. HUVEC human umbilical vein endothelial cells as non-cancerous cell line was used to determine the cancer selectivity of the compounds. Doxorubicin was used as positive control drug. AQQ6 was more cytotoxic than AQQ9 and showed good cytotoxicity against DU-145 prostate cancer cells. Then, molecular pathways related to cytotoxic effects of AQQ6 were investigated with analysis of cell cycle distribution, measurements of cellular ROS levels and apoptosis/necrosis rate with flow cytometry at 1, 2.5 and 5 μM AQQ6 concentrations. According to our findings, AQQ6 induced G0/G1 cell cycle arrest dose-dependently. Also, apoptotic and necrotic cell populations significantly increased with 2.5 and 5 μM AQQ6 concentrations. AQQ6 did not affect cellular ROS levels. In conclusion, AQQ6 shows antiproliferative effects against DU-145 prostate cancer cells, which are mediated through cell cycle arrest and apoptotic and necrotic cell death. Potentially, AQQ6 can be a promising drug candidate for further anticancer research.

In traditional Moroccan medicine, the roots of Pulicaria odora L. (PO) are used against menstrual cramps and intestinal disorders and are highly valued as a spice for their flavor. Several natural compounds are characterized by various biological properties such as antimicrobial, antiviral, antioxidant, anticancer, and anti-aging.

In this study, PO essential oil (EO) is evaluated for the first time for its effect i) on the HTERT gene, a catalytic enzyme that is required for telomerase activity, ii) on the human keratinocyte growth factor (KGF), a secreted protein that could play an important role in the repair of skin injury and that has also been implicated to play a role in other diseases, iii) and on the Sirtuin 1 (SIRT1) which plays an essential role in regulating the cell cycle and energy homeostasis. The EO of PO roots was obtained by hydrodistillation and analyzed by GC/MS. We used Quantitative reverse transcription-polymerase chain reactions (qRT-PCR) to determine the effect of the EO on expression levels of KGF, SIRT1, and HTERT genes in HaCaT cells.

We have identified 22 volatile compounds representing 93.76% of the oil by GC/MS. The oil was dominated by oxygenated compounds with about 93.32% against only 0.44% of terpene hydrocarbons. The KGF expression level in HaCaT cells exposed to EO is found to be significantly higher than resveratrol (RSV) (p<0.05). Also, the EO and resveratrol have induced a similar activity on HTERT and SIRT1 expression (p<0.05).