The therapeutic potential of fatty acid binding protein 4 (FABP4) is widely acknowledged. Currently, there are numerous clinical studies that indicate how fatty acid binding protein 4 inhibitors could be useful in the treatment of various diseases. To identify new and more potent inhibitors, we utilized a two-step computational approach to design novel structures. Through the use of this approach, we were able to identify a new class of FABP4 inhibitors (FABP4i IC50 2.97 to 23.18 µM) that are capable of inhibiting the activity of the protein as low as Arachidonic acid (FABP4i IC50 3.42 ± 0.54 µM). In this communication, we present the detailed structural, biological evaluation as well as the sinthetic procedures of the new pyridazinone-based scaffold FABP4i.

The interconversion of carbon dioxide and the bicarbonate ion is carried out by carbonic anhydrases (CA), which are ubiquitous metalloenzymes with Zn in their active site. Disorder of CA enzymes can cause several diseases such as glaucoma, epilepsy, obesity, and cancer. Many existing drugs have shown effective inhibition of CAs including Acetazolamide, Dorzolamide, Methazolamide, and Valdecoxib.

In order to find new agents inhibiting CAs, two small molecules were synthesized and characterized by the usual spectroscopic methods. The prepared compounds are obtained by the condensation of dimedone and cyclohexanedione with CSI in the presence of methanol as a proton donor.

The synthesized derivatives contain a primary amide group (CONH₂) bio-isostere of the sulfonamide group (SO₂NH₂) which is present in the quasi-totality of CAs inhibitors. The interactions between our new synthesized molecules and the active site of CAII were determined using docking simulation (PDB: 2AW1), the results showed great stability of these compounds inside the active site with the presence of metallic and hydrogen bonds similar to the ones present between CAII and the reference Valdecoxib. Pharmacokinetic properties and toxicity were predicted using in silico tool SwissADME and Molsoft.

Cancer is one of the main leading causes of death worldwide and its treatment is highly complex and known to cause serious side effects for patients. Photodynamic Therapy (PDT) has gained momentum as a promising alternative strategy to overcome or minimize these potential side effects observed in classical therapeutical approaches. This therapy is a minimally invasive treatment that combines a photosensitizer (PS), visible light, and molecular oxygen (³O₂). When excited, the PS interacts with ³O₂ to generate reactive oxygen species (ROS), mainly as singlet oxygen which, in turn, induce cytotoxic effects in cancer cells. In a recent study led by our research group, coelenterazine (Clz) analogues have shown relevant cell-selective toxicity in different cancer cell lines (such as breast, liver, prostate, and neuroblastoma), without cytotoxic effects in the corresponding non-tumoral cells. Based on these results, this work aims to synthesize a new series of Clz-inspired PS derived from pyrazine scaffold, a common precursor in the synthesis of Clz and its structure-related analogues. Herein, we describe some methodological approaches for the synthesis of ten pyrazine-based precursors (with high chemical yields) and their chemical characterization, for the assembly of Clz analogues. Currently, these compounds are being studied for the assembly of new PS with potential application in PDT.

Melanostatin (MIF-1, Fig. 1) is an endogenous tripeptide (Pro-Leu-Gly-NH₂) with several functions within the central nervous system (CNS). It has been widely recognized as a potent and selective positive allosteric modulator (PAM) of the dopamine D₂ receptors (D₂R),[1] with potential biomedical applications in neurological diseases such as Parkinson’s disease (PD). Upon binding to their allosteric binding sites, PAM induce conformational changes that increase binding affinity of orthosteric ligands to the receptor. Comparatively to orthosteric drugs, PAM present several advantages such as high specificity and reduced side effects since they are only effective in the presence of the orthosteric ligand.[2]

Despite its undeniable pharmacological potential in PD, MIF-1 exhibits reduced stability towards CNS-derived peptidases and low gastrointestinal bioavailability,[3,4] hampering oral administration. In this work, the bioisosteric replacement of prolyl residue with non-proteinogenic amino acids is disclosed as a strategy to overcome the unfavorable pharmacokinetic profile of MIF-1 without compromising its PAM activity.

Six novel MIF-1 proline mimetics (Fig. 1) bearing cyclic β-amino acids were designed, synthesized and pharmacologically evaluated. In functional assays at D₂R, one of these peptidomimetics exhibits a superior performance (lower EC₅₀) than MIF-1 at 1 nM. Furthermore, no cytotoxic effect was observed for this compound at 100 µM using differentiated human neuronal SH-SY5Y cells. Further studies are currently underway to determine its chemical stability and in vitro biological permeability. The discovery of a new potent PAM of the D₂R with a safe cytotoxic profile opens new directions for the development of complementary anti-Parkinson therapies.

Cryogels are macroporous hydrogels prepared by cryo-gelation, a green technique that involves a radical polymerization using water as solvent. This method generates an interconnected pore structure that confers to material sponge-like properties. For this peculiarity, cryogels can be used as drug delivery platforms.^1,2

Due to their hydrophobic cavity, allowing non-covalent host-guest inclusion complexation with many hydrophobic molecules, cyclodextrins are well-known and FDA-approved drug delivery carriers.

In this context, we report the preparation of original super-macroporous cryogels starting from HEMA (2-hydroxyethyl methacrylate) and acrylic or styrilic functionalized a, b, or g-cyclodextrin. The macroporous structure cryogels were synthesized by free-radical polymerization in a frozen aqueous system, then purified and dried. All the materials have been extensively characterized by IR, scanning electron microscopy, and thermal gravimetry.

The carriers were successfully tested for the controlled release of antibiotics, anti-inflammatory, and antifungal drugs in the skin for wound healing. For this purpose, the cryogels were loaded with lomefloxacin, piroxicam, and fluconazole drugs. The release of the drugs was efficiently performed in the saline buffer (pH = 7.4), and acidic solution (pH = 3), and the biocompatibility of the newly synthesized sponges was assessed over human fibroblast. The system has several advantages: it is low cost and environmentally friendly, and it has high stability and great versatility since it could be applied to several drugs.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by multiple factors such as the progressive decline of the levels of the neurotransmitter acetylcholine, and the deregulation of the homeostasis of bio-metals such as copper, zinc and iron.

Acetylcholine is hydrolyzed by acetylcholinesterase and butyrylcholinesterase and the current therapeutic strategies are based on the treatment of AD patients with these enzymes’ inhibitors. Although these strategies are focused on disease’s symptomatic relief, recent studies have shown that the long-term use of these drugs may lead to disease modifying benefits.

The deregulation of the bio-metals’ homeostasis has been related to oxidative stress and to the induction of Ab aggregation and of tau hyperphosphorylation and aggregation.

Since AD is a multifactorial disease, discovering a multi-target drug could be an interesting challenge leading to a disease modifying therapy. In this context, mannosylpurines synthesized in our group already showed a potent butyrylcholinesterase (BChE) inhibition. Aiming at the discovery of such multitarget drug candidates, we have synthesized a new series of mannosyl and rhamnosylpurines and evaluated copper chelation and cholinesterases’ inhibition. The results obtained will be presented and discussed.

Nowadays, the discovery of new potential anticancer drugs is one of the main aims of Medicinal Chemistry. There is a wide range of different approaches: new modes of action, new species or new ligands are some of them.

Gold(I) and silver(I) complexes are especially interesting in this field due to their antitumor properties. Complexes with these metal centers also seem to avoid side effects in cancer treatment.

This work consists of two parts. The first one is a chemical part: the design and synthesis of new thiourea-metal complexes. The second one is medical: the study of the anticancer activities of novel compounds. Both thiourea ligands bear a phosphine group in one arm, and a phenyl ring, or a 3,5-di-CF₃, in the other. Although the thioureas used in this research showed no significant cytotoxic activities, all complexes show excellent anticancer activities for Jurkat, A549, and HeLa cell lines.

Amidrazones are known for the broad biological activity of their derivatives (antimicrobial, anti-inflammatory, antiparasitic, antitumor and others). Searching for new drugs twelve new derivatives of N³-substituted amidrazones were obtained in the reaction with cis-1,2,3,6-tetrahydrophthalic anhydride. The structures of obtained linear compounds and 1,2,4-triazole derivatives were confirmed by ¹H NMR, ¹³C NMR and MS. Toxicity and inflammatory activity of obtained compounds (at concentrations of 10, 50 and 100 µg/mL) were studied in human peripheral blood mononuclear cells (PBMC). The influence of new derivatives on cytokine production (TNF-α, IL-6 and IL-10) was examined in PBMC cultures stimulated by LPS. Antiproliferative activity of compounds was studied in PBMC cultures stimulated by phytohaemagglutinin. Minimal inhibitory activity of compounds was studied by broth microdilution method on Gram-positive (S. aureus, M. smegmatis,) and Gram-negative (E. coli, Y. enterocolitica, K. pneumonia) bacterial and fungal C. albicans strain.

Obtained 1,2,4-triazole derivatives were no toxic to PBMC at concentration range 10-100 µg/mL. Only one 1,2,4-triazole derivative showed significant antiproliferative activity at the highest dose. Five 1,2,4-triazole derivatives showed significant, stronger than ibuprofen inhibition of pro-inflammatory TNF-α production at concentrations 10 and 50 µg/mL as well as significant elevation of levels of anti-inflammatory cytokine IL-10 at each used dose. Two linear compounds showed antibacterial activity against Gram-positive bacteria. In conclusion five obtained compounds showed a strong anti-inflammatory effect and deserves further research.

The current study is focused on the combination of pyrazinamide with 6‑aminobenzo[c][1,2]oxaborol-1(3H)-ol, which is a crucial pharmacophore of several antimicrobial agents. The use of benzoxaborole moiety could afford the formation of a spiro adduct between benzoxaborole moiety and 3'-terminal adenosine nucleotide Ade76 of tRNA^Leu. In the form of this spiro adduct, it may potentially inhibit the enzyme leucyl-tRNA synthetase (LeuRS). Large heterocyclic substitution in position 6 of benzoxaborole moiety could lead to the enhanced selectivity of the intended compounds to the bacterial enzyme due to steric clashes with eukaryotic types of LeuRS.

The target compounds were synthesized by condensation of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol with variously substituted heteroaromatic acids that underwent the previous activation.

The synthetic products and the isolated condensation intermediates were subjected to biological in vitro screening against fungi and bacteria, including mycobacteria and in vitro cytotoxicity screening against HepG2 cancer cell line. Some of the compounds showed moderate antimycobacterial activity with persisted low toxicity.

Glioblastoma (GBM) is the most frequent and lethal primary brain tumor, rapidly growing and spreading into nearby healthy tissues with devastating effects for patients and those around them. GBM has currently no cure, being the average survival of GBM patients after diagnosis limited to a few months. The drug resistance ability and fast regrowth of GBM are the main problems related to current treatments. The intrinsic high heterogeneity and the microenvironment of these tumors are some of the reasons for the low efficacy of the available treatments. Therefore, new therapy alternatives for this highly aggressive brain cancer are urgently needed. Chalcones are synthetic or naturally occurring compounds that have been widely investigated for cancer targeting. Thus, in this work, chalcone derivatives were tested regarding their inhibitory activity and specificity toward GBM cell lines. The chalcone derivative with the most potent and selective cytotoxic effects on GBM cells was further investigated regarding its ability to reduce critical hallmark features of GBM. This derivative showed to successfully reduce key targets for cancer treatment, namely the invasion and proliferation capacity of tumor cells by inducing cell cycling arrest and cell apoptosis. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was successfully encapsulated into liposomes. Therapeutic concentrations were incorporated re-taining the potent in vitro growth inhibitory effect of the selected chalcone. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.