Search

In the last years, 5-pyrazolyl ureas and 5-aminopyrazoles have been investigated for their antiangiogenetic properties and their potential interaction with the ubiquitous Ca 2+ binding protein Calreticulin. Based on the structure of the active compounds I and GeGe-3, novel 5-arylamino pyrazoles 2 and 3 were synthesized through a stepwise procedure. In MTT assays, all the new derivatives proved to be non-cytotoxic against eight different tumor cell lines, normal fibroblasts, and endothelial cells. Furthermore, selected derivatives showed relevant antiangiogenetic properties, resulting more effective than reference molecules I and GeGe-3 in inhibiting HUVEC endothelial tube formation. 5-Arylamino pyrazoles 2a and 2d were identified as the most interesting compounds and significantly prevented tube formation of tumor secretome-stimulated HUVEC. Furthermore, the two compounds inhibited HUVEC migration in wound healing assay and altered cell invasion capability. Additionally, 2a and 2d strongly affected Ca 2+ mobilization and cytoskeletal organization of HUVEC cells, being as active as the reference compound GeGe-3. Differently from previous studies, molecular docking simulations suggested a poor affinity of 2a towards Calreticulin, one of the interacting partners of the lead compound GeGe-3. Collectively, this new amino-pyrazole library further extends the structure-activity relationships of the previously prepared derivatives and confirmed the biological attractiveness of this chemical scaffold as antiangiogenetic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

G-protein-coupled receptors (GPCRs) represent a family of druggable targets when treating several diseases and continue to be a leading part of the drug discovery process. Trace amine-associated receptors (TAARs) are GPCRs involved in many physiological functions with TAAR1 having important roles within the central nervous system (CNS). By using homology modeling methods, the responsiveness of TAAR1 to endogenous and synthetic ligands has been explored. In addition, the discovery of different chemo-types as selective murine and/or human TAAR1 ligands has helped in the understanding of the species-specificity preferences. The availability of TAAR1-ligand complexes sheds light on how different ligands bind TAAR1. TAAR5 is considered an olfactory receptor but has specific involvement in some brain functions. In this case, the drug discovery effort has been limited. Here, we review the successful computational efforts developed in the search for novel TAAR1 and TAAR5 ligands. A specific focus on applying structure-based and/or ligand-based methods has been done. We also give a perspective of the experimental data available to guide the future drug design of new ligands, probing species-specificity preferences towards more selective ligands. Hints for applying repositioning approaches are also discussed.

Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS, JP, and TV have a proprietary interest in selective PDE4D inhibitors for the treatment of demyelinating disorders and neurodegenerative disorders. RR, EF, OB, CB, and JP have a proprietary interest in the use of Gebr32a. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. Hence, ensuring access to novel and improved chemotherapeutic agents is imperative for patients grappling with this severe ailment. Pyrazole and its fused systems derived thereof are heteroaromatic moieties widely employed in medicinal chemistry to develop effective drugs for various therapeutic areas, including inflammation, pain, oxidation, pathogens, depression, and fever. In a previous study, we described the biochemical properties of a newly synthesized group of imidazo-pyrazole compounds. In this paper, to improve our knowledge of the pharmacological properties of these molecules, we conduct a differential proteomic analysis on a human melanoma cell line treated with one of these imidazo-pyrazole derivatives. Our results detail the changes to the SKMEL-28 cell line proteome induced by 24, 48, and 72 h of 3e imidazo-pyrazole treatment. Notably, we highlight the down-regulation of the Ras-responsive element binding protein 1 (RREB1), a member of the zinc finger transcription factors family involved in the tumorigenesis of melanoma. RREB1 is a downstream element of the MAPK pathway, and its activation is mediated by ERK1/2 through phosphorylation.

In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1 H -pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2 + -binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 μM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1-4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1 ); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2 ); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3 ); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4 ). All new derivatives 1-4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.

Sirtuins (SIRTs) are classified as class III histone deacetylases (HDACs), a family of enzymes that catalyze the removal of acetyl groups from the ε-N-acetyl lysine residues of histone proteins, thus counteracting the activity performed by histone acetyltransferares (HATs). Based on their involvement in different biological pathways, ranging from transcription to metabolism and genome stability, SIRT dysregulation was investigated in many diseases, such as cancer, neurodegenerative disorders, diabetes, and cardiovascular and autoimmune diseases. The elucidation of a consistent number of SIRT-ligand complexes helped to steer the identification of novel and more selective modulators. Due to the high diversity and quantity of the structural data thus far available, we reviewed some of the different ligands and structure-based methods that have recently been used to identify new promising SIRT1/2 modulators. The present review is structured into two sections: the first includes a comprehensive perspective of the successful computational approaches related to the discovery of SIRT1/2 inhibitors (SIRTIs); the second section deals with the most interesting SIRTIs that have recently appeared in the literature (from 2017). The data reported here are collected from different databases (SciFinder, Web of Science, Scopus, Google Scholar, and PubMed) using "SIRT", "sirtuin", and "sirtuin inhibitors" as keywords.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10 - 22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC 50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N -acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a - o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients.

The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2-5, differently decorated on the pyrazole nucleus. All the derivatives were tested by MTT assays and proved to be non-cytotoxic against eight different tumor cell lines and normal fibroblasts. An EdU proliferation assay was carried out on human foreskin fibroblasts and VEGF stimulated human umbilical vein endothelial cells which confirmed the absence of cytotoxicity of the compounds on human cells up to 20 μM concentration. To evaluate the influence of the newly synthesized pyrazoles on MAPK and PI3K signaling pathways, the phosphorylation of ERK1/2 and Akt was analyzed by Western blots from HFF and HUVEC cell lysates stimulated with growth factors in the presence or absence of the compounds. Pyrazoles 3b and 3c showed a significant inhibition of Akt phosphorylation in both tested cell lines with lower phosphorylation levels than the reference compound GeGe-3 in HUVEC. Furthermore, derivatives 2 and 3 appeared to strongly affect the migration of HFF cells in a wound healing assay, confirming their potential ability to interfere with the angiogenesis process. The new pyrazole library extends the structure-activity relationships of the previously isolated compounds and highlights the attractiveness of this chemical class for pathological cell migration and angiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Neuroblastoma (NB) is a childhood cancer, commonly treated with drugs, such as etoposide (ETO), whose efficacy is limited by the onset of resistance. Here, aiming at identifying new treatments for chemo-resistant NB, the effects of two synthesized imidazo-pyrazoles (IMPs) ( 4G and 4I ) were investigated on ETO-sensitive (HTLA-230) and ETO-resistant (HTLA-ER) NB cells, detecting 4I as the more promising compound, that demonstrated IC 50 values lower than those of ETO on HTLA ER. Therefore, to further improve the activity of 4I , we developed 4I -loaded palmitic acid (PA) and polystyrene-based (P5) cationic nanoparticles (P5PA-4I NPs) with high drug loading (21%) and encapsulation efficiency (97%), by a single oil-in-water emulsification technique. Biocompatible PA was adopted as an emulsion stabilizer, while synthesized P5 acted as an encapsulating agent, solubilizer and hydrophilic-lipophilic balance (HLB) improver. Optic microscopy and cytofluorimetric analyses were performed to investigate the micromorphology, size and complexity distributions of P5PA-4I NPs, which were also structurally characterized by chemometric-assisted Fourier transform infrared spectroscopy (FTIR). Potentiometric titrations allowed us to estimate the milliequivalents of PA and basic nitrogen atoms present in NPs. P5PA-4I NPs afforded dispersions in water with excellent buffer capacity, essential to escape lysosomal degradation and promote long residence time inside cells. They were chemically stable in an aqueous medium for at least 40 days, while in dynamic light scattering (DLS) analyses, P5PA-4I showed a mean hydrodynamic diameter of 541 nm, small polydispersity (0.194), and low positive zeta potentials (+8.39 mV), assuring low haemolytic toxicity. Biological experiments on NB cells, demonstrated that P5PA-4I NPs induced ROS-dependent cytotoxic effects significantly higher than those of pristine 4I , showing a major efficacy compared to ETO in reducing cell viability in HTLA-ER cells. Collectively, this 4I -based nano-formulation could represent a new promising macromolecular platform to develop a new delivery system able to increase the cytotoxicity of the anticancer drugs.

Aiming at developing a dermal formulation against melanoma, the synthesized imidazo-pyrazoles 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (3-methoxy-4-phenoxy-benzylidene)-hydrazide ( 4G ) and 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (4-benzyloxy-3-methoxy-benzylidene)-hydrazide ( 4I ) were screened on patient-isolated melanoma cells (MEOV NT) and on Vemurafenib (PLX4032)-resistant (MEOV PLX-R) ones. Since 4I on MEOV PLX-R cells was 1.4-fold more effective than PLX, a hydrogel formulation containing 4I (R4HG-4I) was prepared in parallel with an empty R4-based hydrogel (R4HG) using a synthesized antibacterial resin (R4) as gelling agent. Thanks to its high hydrophilicity, porosity (85%), and excellent swelling capability (552%), R4 allowed to achieve R4HG and R4HG-4I with high equilibrium degree of swelling (EDS) and equilibrium water content (EWC). Chemometric-assisted ATR-FTIR analyses confirmed the chemical structure of swollen and fully dried (R4HG-D and R4HG-4I-D) hydrogels. The morphology of R4HG-D and R4HG-4I-D was examined by optical microscopy and SEM, while UV-vis analyses were carried out to obtain the drug loading (DL%) and the encapsulation efficiency (EE%) of R4HG-4I. Potentiometric titrations were performed to determine the equivalents of NH 3 + in both R4HG and R4HG-4I. The swelling and water release profiles of both materials and related kinetics were assessed by equilibrium swelling rate and water loss studies, respectively, while their biodegradability over time was assessed by in vitro degradation experiments determining their mass loss. Rheological experiments established that both R4HG and R4HG-4I are shear-thinning Bingham pseudoplastic fluids with low yield stress, thus assuring easy spreadability in a future topical application. Release studies evidenced a sustained and quantitative release of 4I governed mainly by diffusion. Upon favorable results from further experiments in a more realistic 3D model of melanoma, R4HG-4I could represent a starting point to develop new topical therapeutic options to adjuvate the treatments of melanoma cells also when resistant to currently available drugs.

In previous studies, we synthesized different imidazo-pyrazoles 1 and 2 with interesting anticancer, anti-angiogenic and anti-inflammatory activities. To further extend the structure-activity relationships of imidazo-pyrazole scaffold and to identify novel antiproliferative/anti-inflammatory agents potentially active with multi-target mechanisms, a library of compounds 3-5 has been designed and synthesized. The chemical modifications characterizing the novel derivatives include: i) decoration of the catechol ring with groups with different electronic, steric and lipophilic properties (compounds 3); ii) insertion of a methyl group on C-6 of imidazo-pyrazole scaffold (compounds 4); iii) shift of the acylhydrazonic substituent from position 7 to 6 of the imidazo-pyrazole substructure (compounds 5). All synthesized compounds were tested against a panel of cancer and normal cell lines. Derivatives 3 a, 3 e, 4 c, 5 g and 5 h showed IC 50 values in the low micromolar range against selected tumor cell lines and proved to have antioxidant properties, being able to inhibit ROS production in human platelet. In silico calculation predicted favourable drug-like and pharmacokinetic properties for the most promising compounds. Furthermore, molecular docking and molecular dynamic simulations suggested the ability of most active derivative 3 e to interact with colchicine binding site in the polymeric tubulin α/tubulin β/stathmin4 complex., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The populations usually attributed to Solenopsisbivonae (Tineo) M.B.Crespo, Serra & A.Juan are investigated from a taxonomical and morphological viewpoint. Within this species complex, four new subspecies occurring in Sicily and Calabria are recognized, such as subsp. bivonae, subsp. madoniarum, subsp. peloritana and subsp. brutia. In addition, a new species from Cyprus described as S.meikleana and S.bacchettae from Sardinia must be included in this group. The synonymy, typification, description, seed testa morphology, chorology, ecology, illustrations, conservation status, and examined specimens for each taxon are provided. Besides, the analytical keys, distribution maps, and phytosociological arrangement regarding these taxa are given too., Competing Interests: No conflict of interest was declared., (Salvatore Brullo, Cristian Brullo, Salvatore Cambria, Valeria Tomaselli, Alessandro Crisafulli, Giuseppe Siracusa, Pietro Minissale, Gianpietro Giusso del Galdo.)

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery.

Inhibition of phosphodiesterase 4D (PDE4D) enzymes has been investigated as therapeutic strategy to treat memory problems in Alzheimer's disease (AD). Although PDE4D inhibitors are effective in enhancing memory processes in rodents and humans, severe side effects may hamper their clinical use. PDE4D enzymes comprise different isoforms, which, when targeted specifically, can increase treatment efficacy and safety. The function of PDE4D isoforms in AD and in molecular memory processes per se has remained unresolved. Here, we report the upregulation of specific PDE4D isoforms in transgenic AD mice and hippocampal neurons exposed to amyloid-β. Furthermore, by means of pharmacological inhibition and CRISPR-Cas9 knockdown, we show that the long-form PDE4D3, -D5, -D7, and -D9 isoforms regulate neuronal plasticity and convey resilience against amyloid-β in vitro. These results indicate that isoform-specific, next to non-selective, PDE4D inhibition is efficient in promoting neuroplasticity in an AD context. Therapeutic effects of non-selective PDE4D inhibitors are likely achieved through actions on long isoforms. Future research should identify which long PDE4D isoforms should be specifically targeted in vivo to both improve treatment efficacy and reduce side effects., (© 2023. The Author(s).)

Imidazolidine-2-thione substructure represents a pharmaceutically attractive scaffold, being included in different antimicrobial, anticancer and pesticide agents. To further evaluate the pharmaceutical potential of this chemical moiety, imidazolidine-2-thione was reacted with atypical Vilsmeier adducts, obtained by the condensation between dimethylacetamide and various acyl chlorides endowed with different electronic and steric properties. The formation of mono-acylated or di-acylated thiourea derivatives emerged to be affected by the nature of the considered acyl chloride reagent. Computational semi-empirical simulations were carried out to rationalize the relevant factor influencing the outcome of the reaction. As acylthioureas are pharmacologically relevant compounds, the chemical versatility of mono-acylated derivatives were evaluated by reacting benzoyl imidazolidin-2-thione with acyl chlorides. A small library of asymmetric di-acylthioureas was prepared and the obtained derivatives did not show any cytotoxicity on SKOV-3 and MCF-7 cancer cell lines. Additionally, in silico studies predicted good pharmacokinetics properties and promising drug-like characteristics for mono- and di-acylated thioureas. These considerations further support the value of the prepared compounds as interesting non-cytotoxic chemical scaffold useful in the medicinal chemistry field., (© 2022. The Author(s).)

Sirtuin isoform 2 (SIRT2) is one of the seven sirtuin isoforms present in humans, being classified as class III histone deacetylases (HDACs). Based on the high sequence similarity among SIRTs, the identification of isoform selective modulators represents a challenging task, especially for the high conservation observed in the catalytic site. Efforts in rationalizing selectivity based on key residues belonging to the SIRT2 enzyme were accompanied in 2015 by the publication of the first X-ray crystallographic structure of the potent and selective SIRT2 inhibitor SirReal2. The subsequent studies led to different experimental data regarding this protein in complex with further different chemo-types as SIRT2 inhibitors. Herein, we reported preliminary Structure-Based Virtual Screening (SBVS) studies using a commercially available library of compounds to identify novel scaffolds for the design of new SIRT2 inhibitors. Biochemical assays involving five selected compounds allowed us to highlight the most effective chemical features supporting the observed SIRT2 inhibitory ability. This information guided the following in silico evaluation and in vitro testing of further compounds from in-house libraries of pyrazolo-pyrimidine derivatives towards novel SIRT2 inhibitors ( 1 - 5 ). The final results indicated the effectiveness of this scaffold for the design of promising and selective SIRT2 inhibitors, featuring the highest inhibition among the tested compounds, and validating the applied strategy.

The impact of innovative technologies on the target discovery has been employed here to characterize the interactome of STIRUR 41, a promising 3-fluoro-phenyl-5-pyrazolyl-urea derivative endowed with anti-cancer activity, on neuroblastoma-related cells. A drug affinity responsive target stability-based proteomic platform has been optimized to elucidate the molecular mechanism at the basis of STIRUR 41 action, together with immunoblotting analysis and in silico molecular docking. Ubiquitin Specific Protease 7 (USP-7), one of the deubiquitinating enzymes which protect substrate proteins from proteasomal degradation, has been identified as the most affine STIRUR 41 target. As further demonstrated by in vitro and in-cell assays, STIRUR 41 was able to inhibit both the enzymatic activity of USP-7 and its expression levels in neuroblastoma-related cells, thus laying an encouraging base for the blockade of USP-7 downstream signaling.

During the last years, we developed a large library of new selective phosphodiesterase 4D inhibitors, maintaining the catechol portion of the well-known PDE4 inhibitor Rolipram, featuring different substitutions in place of the lactam group of this reference compound. Based on the X-ray analysis of PDE4 inhibitors (PDE4Is) previously synthesized by us and of naphthyridine- and naphthyridinone-containing derivatives exhibiting PDE4 inhibitory ability described in the literature, we designed and synthesized new compounds 1-3. All of them were screened in silico as putative PDE4Is, via molecular docking studies to exploit structural variation at the catechol group to gain further contacts especially with the flat aromatic residues (Phe506 and Phe538) of enzyme. Subsequent in silico prediction of ADMET properties and in vitro biological assays on platelets and endothelial cells are in good agreement with our previous data concerning the antioxidant/anti-inflammatory activity exhibited by our previous PDE4Is and similarly to other well-known PDE4Is., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

A pyrazole nucleus is an easy-to-prepare scaffold with large therapeutic potential. Consequently, the search for new pyrazole-based compounds is of great interest to the academic community as well as industry. In the last ten years, a large number of papers and reviews on the design, synthesis, and biological evaluation of different classes of pyrazoles and many pyrazole-containing compounds have been published. However, an overview of pyrazole derivatives bearing a free amino group at the 3, 4, or 5 position (namely, 3-aminopyrazoles, 4-aminopyrazoles, and 5-aminopyrazoles, respectively) and their biological properties is still missing, despite the fact that aminopyrazoles are advantageous frameworks able to provide useful ligands for receptors or enzymes, such as p38MAPK, and different kinases, COX and others, as well as targets important for bacterial and virus infections. With the aim to fill this gap, the present review focuses on aminopyrazole-based compounds studied as active agents in different therapeutic areas, with particular attention on the design and structure-activity relationships defined by each class of compounds. In particular, the most relevant results have been obtained for anticancer/anti-inflammatory compounds, as the recent approval of Pirtobrutinib demonstrates. The data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "aminopyrazole" as the keyword.

Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the Staphylococcus and Enterococcus genera, with the lead compound ( 9 ) reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound 9 on Staphylococcus aureus MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.

Neuroblastoma (NB) is a severe form of tumor occurring mainly in young children and originating from nerve cells found in the abdomen or next to the spine. NB needs more effective and safer treatments, as the chance of survival against the aggressive form of this disease are very small. Moreover, when current treatments are successful, they are often responsible for unpleasant health problems which compromise the future and life of surviving children. As reported, cationic macromolecules have previously been found to be active against bacteria as membrane disruptors by interacting with the negative constituents of the surface of cancer cells, analogously inducing depolarization and permeabilization, provoking lethal damage to the cytoplasmic membrane, and cause loss of cytoplasmic content and consequently, cell death. Here, aiming to develop new curative options for counteracting NB cells, pyrazole-loaded cationic nanoparticles (NPs) (BBB4-G4K and CB1H-P7 NPs), recently reported as antibacterial agents, were assayed against IMR 32 and SHSY 5Y NB cell lines. Particularly, while BBB4-G4K NPs demonstrated low cytotoxicity against both NB cell lines, CB1H-P7 NPs were remarkably cytotoxic against both IMR 32 and SHSY 5Y cells (IC 50 = 0.43-0.54 µM), causing both early-stage (66-85%) and late-stage apoptosis (52-65%). Interestingly, in the nano-formulation of CB1H using P7 NPs, the anticancer effects of CB1H and P7 were increased by 54-57 and 2.5-4-times, respectively against IMR 32 cells, and by 53-61 and 1.3-2 times against SHSY 5Y cells. Additionally, based on the IC 50 values, CB1H-P7 was also 1-12-fold more potent than fenretinide, an experimental retinoid derivative in a phase III clinical trial, with remarkable antineoplastic and chemopreventive properties. Collectively, due to these results and their good selectivity for cancer cells (selectivity indices = 2.8-3.3), CB1H-P7 NPs represent an excellent template material for developing new treatment options against NB.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the effort to obtain multitarget compound interfering with inflammation, oxidative stress, and tumorigenesis, we synthesized a small library of pyrazole compounds, selecting 4a , 4f , and 4g as the most noteworthy being IC 50 against platelet ROS production induced by thrombin of about 10 µM. The in vitro antioxidant potential of the three molecules was evaluated, and since they show a remarkable antioxidative activity, their effect on several parameter indicative of oxidative status and on the efficiency of the aerobic metabolism was tested. The three molecules strongly inhibit superoxide anion production, lipid peroxidation, NADPH oxidase activity and almost restore the oxidative phosphorylation efficiency in thrombin-stimulated platelet, demonstrating a protective effect against oxidative stress. This effect was confirmed in endothelial cell in which 4a , 4f , and 4g show an interesting inhibition activity on H 2 O 2 -stimulated EA.hy926 cells. At last, antiproliferative activity of 4a , 4f , and 4g was submitted to a large screening at the NCI. The molecules show interesting anticancer activity, among them the most remarkable is 4g able to strongly inhibit the proliferation of both solid tumor and leukemia cells lines. In conclusion, all the three newly synthetized pyrazoles show remarkable antioxidant and antiproliferative effect worthy of further study.

Here, to develop new topical antibacterial formulations to treat staphylococcal infections, two pyrazoles ( 3c and 4b ) previously reported as antibacterial agents, especially against staphylococci, were formulated as hydrogels (R1-HG-3c and R1HG-4b) using a cationic polystyrene-based resin (R1) and here synthetized and characterized as gelling agents. Thanks to the high hydrophilicity, high-level porosity, and excellent swelling capabilities of R1, R1HG-3c and R1HG-4b were achieved with an equilibrium degree of swelling (EDS) of 765% (R1HG-3c) and 675% (R1HG-4b) and equilibrium water content (EWC) of 88% and 87%, respectively. The chemical structure of soaked and dried gels was investigated by PCA-assisted attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy, while their morphology was investigated by optical microscopy. Weight loss studies were carried out with R1HG-3c and R1HG-4b to investigate their water release profiles and the related kinetics, while their stability was evaluated over time both by monitoring their inversion properties to detect possible impairments of the 3D network and by PCA-assisted ATR-FTIR spectroscopy to detect possible structural changes. The flow and dynamic rheological characterization of the gels was assessed by determining their viscosity vs. shear rate, applying the Cross rheological equation to achieve the curves of shear stress vs. shear rate, and carrying out amplitude and frequency sweep experiments. Finally, their content in NH 3 + groups was determined by potentiometric titrations. Due to their favorable physicochemical characteristic and the antibacterial effects of 3c and 4b possibly improved by the cationic R1, the pyrazole-enriched gels reported here could represent new weapons to treat severe skin and wound infections sustained by MDR bacteria of staphylococcal species.

The aims of this study were to investigate the effects of different equilibration times with cryoprotectants on viability and metaphase plate morphology of vitrified-warmed porcine mature oocytes (Experiment 1) and to evaluate the effects of supplementation with 10 -9 M melatonin during in vitro maturation on these parameters (Experiment 2). In Experiment 1, 2,392 mature oocytes were vitrified using different equilibration times of oocytes with cryoprotectants (3, 10, 15, 20, 30, 40, 60 and 80 min). Fresh oocytes matured in vitro for 44 hr (n = 509) were used as controls. In Experiment 2, a total of 573 COCs were used. COCs were matured with 10 -9 M melatonin supplementation or without melatonin (control). Some oocytes from each group were vitrified with a 60-min equilibration time with cryoprotectants according to the results of Experiment 1. The remaining oocytes from each maturation group were used as fresh control groups. In both experiments, oocytes were stained with 2',7'-dichlorodihydrofuorescein diacetate and Hoechst 33342 to assess viability and metaphase plate morphology, respectively. Vitrification and warming affected (p < .01) oocyte viability compared with controls, which were all viable after 44 hr of IVM. In Experiment 1, the longer the equilibration time with cryoprotectants, the higher the viability. Oocytes equilibrated for 60 and 80 min had the highest (p < .05) viability and similar metaphase plate characteristics to the fresh control oocytes. In Experiment 2, supplementation with melatonin during in vitro maturation had no effect on oocyte viability or metaphase plate morphology of vitrified-warmed oocytes. In conclusion, under our experimental conditions, vitrified porcine mature oocytes equilibrated with cryoprotectants for 60 or 80 min exhibited the highest viability and similar metaphase plate characteristics to fresh controls. Furthermore, supplementation with 10 -9 M melatonin during in vitro maturation had no effect on these parameters., (© 2022 The Authors. Reproduction in Domestic Animals published by Wiley-VCH GmbH.)

Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. In high-income countries this disease has a survival rate approaching 100%, while in low- and middle-income countries the prognosis is fatal for about 80% of cases. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms of the disease, surgical removal of the entire globe and its intraocular contents (enucleation) is, unfortunately, necessary, whereas in other cases, conventional chemotherapy is normally used. To overcome the side-effects and reduced efficacy of traditional chemotherapic drugs, nanodelivery systems that ensure a sustained drug release and manage to reach the target site have more recently been developed. This review takes into account the current use and advances of nanomedicine in the treatment of retinoblastoma and discusses nanoparticulate formulations that contain conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed.

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds 2 - 7 ). In detail, new derivatives 2 - 7 were differently decorated in C3, C4 and C5 positions. An in silico study predicted pyrazoles 2 - 7 to exert good drug-like and pharmacokinetic properties. Compounds 3c and 4b were endowed with moderate, but nanotechnologically improvable activity against multidrug-resistant (MDR) clinical isolates of Gram-positive species, especially of the Staphylococcus genus (MICs = 32-64 µg/mL). In addition, derivatives 3c and 4a showed moderate activities against Mycobacterium tuberculosis and 4a evidenced activity also against MDR strains. Overall, the collected evidence supported that, upon nano-formulation with proper polymer matrices, the new synthesized compounds could provide new pyrazole-based drug delivery systems with an enhanced and enlarged-spectrum of antibacterial activity.

Molecules containing the pyrazole nucleus are widely reported as promising candidates to develop new antimicrobial compounds against multidrug-resistant (MDR) bacteria, where available antibiotics may fail. Recently, aiming at improving the too-high minimum inhibitory concentrations (MICs) of a pyrazole hydrochloride salt (CB1H), CB1H-loaded nanoparticles (CB1H-P7 NPs) were developed using a potent cationic bactericidal macromolecule (P7) as polymer matrix. Here, CB1H-P7 NPs have been successfully tested on several clinical isolates of Gram-positive and Gram-negative species, including relevant MDR strains. CB1H-P7 NPs displayed very low MICs (0.6-4.8 µM), often two-fold lower than those of P7, on 34 out of 36 isolates tested. Upon complexation, the antibacterial effects of pristine CB1H were improved by 2-16.4-fold, and, unexpectedly, also the already potent antibacterial effects of P7 were 2-8 times improved against most of bacteria tested when complexed with CB1H. Time-killing experiments performed on selected species established that CB1H-P7 NPs were bactericidal against Staphylococcus aureus , Escherichia coli and Pseudomonas aeruginosa . Selectivity indices values up to 2.4, determined by cytotoxicity experiments on human keratinocytes, suggested that CB1H-P7 NPs could be promising for counteracting serious infections sustained by most of the isolates tested in this study.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

A syntaxonomical revision of the Isoëto-Nanojuncetea class for the Sicilian territory is provided. This syntaxon gathers the ephemeral herbaceous hygrophilous plant communities linked to periodically submerged soils, widely distributed in the European, circum-Mediterranean and Macaronesian territories. Within this class, two orders are recognized, lsoëtetalia , with a prevalently Mediterranean distribution, and Nanocyperetalia chiefly occurring in the central-European and Atlantic territories, with scattered and marginal occurrence in the Mediterranean area. The order Isoëtetalia in Sicily is represented by four alliances, i.e., Isoëtion , Preslion cervinae , Cicendio-Solenopsion laurentiae and Agrostion salmanticae , while within Nanocyperetalia three alliances can be recognized, namely Nanocyperion , Verbenion supinae and Lythrion tribracteati . Overall, 32 plant communities are recognized, 11 of which are described for the first time. Each higher rank syntaxa and related associations are examined from a nomenclatural, floristic, ecological and chorological point of view. In particular, the associations were processed using cluster analysis in order to highlight the correlations between them. Regarding the floristic aspects, a checklist of the species occurring in the phytosociological relevés is provided, as well as a new combination concerning Solenopsis gasparrinii , a critical species of the Sicilian flora, is proposed.

A pyrazole derivative (CB1) was previously evaluated in vivo for various pharmacological activities (with the exception of antimicrobial effects), using DMSO as the administrative medium, mainly due to its water insolubility. Considering the global necessity for new antimicrobial agents, CB1 attracted our attention as a candidate to meet this need, mainly because the secondary amine group in its structure would make it possible to obtain its hydrochloride salt (CB1H), thus effortlessly solving its water-solubility drawbacks. In preliminary microbiologic investigations on Gram-negative and Gram-positive bacteria, CB1H displayed weak antibacterial effects on MDR isolates of Gram-positive species, nonetheless better than those displayed by the commonly-used available antibiotics. Therefore, aiming at improving such activity and extending the antibacterial spectrum of CB1H to Gram-negative pathogens, in this first work CB1 was strategically formulated in nanoparticles using a cationic copolymer (P7) previously developed by us, possessing potent broad-spectrum bactericidal activity. Using the nanoprecipitation method, CB1H-loaded polymer nanoparticles (CB1H-P7 NPs) were obtained, which were analyzed by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy to confirm the successful loading. Additionally, CB1H-P7 NPs were fully characterized in terms of morphology, size, polydispersity indices, surface charge, DL%, and EE%, as well as release and potentiometric profiles.

Although the antimicrobial potency of the pyrazole nucleus is widely reported, the antimicrobial effects of the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4), found to be active against several other conditions, have never been investigated. Considering the worldwide need for new antimicrobial agents, we thought it noteworthy to assess the minimum inhibitory concentration (MICs) of BBB4 but, due to its scarce water-solubility, unequivocal determinations were tricky. To obtain more reliable MICs and to obtain a substance also potentially applicable in vivo, we recently prepared water-soluble, BBB4-loaded dendrimer nanoparticles (BBB4-G4K NPs), which proved to have physicochemical properties suitable for clinical application. Here, with the aim of developing a new antibacterial agent based on BBB4, the BBB4-G4K NPs were tested on several strains of different species of the Staphylococcus genus. Very low MICs (1.5-3.0 µM), 15.5-124.3-fold lower than those of the free BBB4, were observed against several isolates of S. aureus and S. epidermidis , the most pathogenic species of this genus, regardless of their resistance patterns to antibiotics. Aiming at hypothesizing a clinical use of BBB4-G4K NPs for staphylococcal skin infections, cytotoxicity experiments on human keratinocytes were performed; it was found that the nano-manipulated BBB4 released from BBB4-G4K NPs ( LD 50 138.6 µM) was 2.5-fold less cytotoxic than the untreated BBB4 (55.9 µM). Due to its physicochemical and biological properties, BBB4-G4K NPs could be considered as a promising novel therapeutic option against the very frequent staphylococcal skin infections.

Based on biological results of previous synthesized pyrazolyl ureas able to interfere with angiogenesis process, we planned and synthesized the new benzyl-urea derivatives 2-4; some of them showed an interesting anti-proliferative profile and particularly 4e potently inhibited HUVEC proliferation. To shed light on the mechanism of action of 4e, its interactome has been deeply inspected to identify the most prominent protein partners, mainly taking into account kinome and phosphatome, through drug affinity responsive target stability experiments, followed by targeted limited proteolysis analysis. From these studies, PP1γ emerged as the most reliable 4e potential target in HUVEC. Molecular docking simulations on PP1γ were carried out to predict 4e binding mode. To assess its potential anti-angiogenic effect, 4e was tested in vitro to verify interference on kinase and phosphate activities. Overall, our results evidenced for 4e an interesting anti-angiogenic action, probably due to its action at intracellular level on PP1γ signalling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.

The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells. Particularly, Gege3 has been able to notably prevent the effects of Ac2-26, the ANXA1 mimetic peptide, and of PC-derived EVs on endothelial cells motility, angiogenesis, and calcium release. Furthermore, this compound also inhibited the translocation of ANXA1 to the plasma membrane, otherwise induced by the same ANXA1-dependent extracellular stimuli. Moreover, these effects have been mediated by the indirect inhibition of protein kinase Cα (PKCα), which generally promotes the phosphorylation of ANXA1 on serine 27. Indeed, by the subtraction of intracellular calcium levels, the pathway triggered by PKCα underwent a strong inhibition leading to the following impediment to the ANXA1 localization at the plasma membrane, as revealed by confocal and cytofluorimetry analysis. Thus, Gege3 appeared an attractive molecule able to prevent the paracrine effects of PC cells deriving ANXA1 in the tumor microenvironment.

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

2-(4-Bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4) was synthetized and successfully evaluated concerning numerous biological activities, except for antimicrobial and cytotoxic effects. Due to the antimicrobial effects possessed by pyrazole nucleus, which have been widely reported, and the worldwide need for new antimicrobial agents, we thought it would be interesting to test BBB4 and to evaluate its possible antibacterial effects. Nevertheless, since it is water-insoluble, the future clinical application of BBB4 will remain utopic unless water-soluble BBB4 formulations are developed. To this end, before implementing biological evaluations, BBB4 was herein re-synthetized and characterized, and a new water-soluble BBB4-based nano-formulation was developed by its physical entrapment in a biodegradable non-cytotoxic cationic dendrimer (G4K), without recovering harmful solvents as DMSO or surfactants. The obtained BBB4 nanoparticles (BBB4-G4K NPs) showed good drug loading (DL%), satisfying encapsulation efficiency (EE%), and a biphasic quantitative release profile governed by first-order kinetics after 24 h. Additionally, BBB4-G4K was characterized by ATR-FTIR spectroscopy, NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While, before the nanotechnological manipulation, BBB4 was completely water-insoluble, in the form of BBB4-G4K NPs, its water-solubility resulted in being 105-fold higher than that of the pristine form, thus establishing the feasibility of its clinical application.

In recent years, 5-pyrazolyl-ureas have mostly been known for their attractive poly-pharmacological outline and, in particular, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl) ureido)-1H-pyrazole-4-carboxylate (named GeGe-3) has emerged as a capable anti-angiogenic compound. This paper examines its interactome by functional proteomics using a label-free mass spectrometry based platform, coupling Drug Affinity Responsive Target Stability and targeted Limited Proteolysis-Multiple Reaction Monitoring. Calreticulin has been recognized as the GeGe-3 principal target and this evidence has been supported by immunoblotting and in silico molecular docking. Furthermore, cell studies have shown that GeGe-3 lowers cell calcium mobilization, cytoskeleton organization and focal adhesion kinase expression, thus linking its biological potential to calreticulin binding and, ultimately, shedding light on the reasonable action mechanism of this molecule as an anti-angiogenic factor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

(1) Background: different previously synthesized pyrazoles and imidazo-pyrazoles showed interesting anti-angiogenic action, being able to interfere with ERK1/2, AKT and p38MAPK phosphorylation in different manners and with different potency; (2) Methods: here, a new small compound library, endowed with the same differently decorated chemical scaffolds, has been synthetized to obtain new agents able to inhibit different pathways involved in inflammation, cancer and human platelet aggregation. (3) Results: most of the new synthesized derivatives resulted able to block ROS production, platelet aggregation and p38MAPK phosphorylation both in platelets and Human Umbilical Vein Endothelial cells (HUVEC). This paves the way for the development of new agents with anti-angiogenic activity.

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.

Background: Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancers; it has shown an important role in metastasis formation, cell migration, invasion and angiogenesis and consequently it has been proposed as a potential target in cancer therapy, particularly in a metastatic phase. In recent years, different investigations have highlighted the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to the cardiac function or viral infection., Methods: An extensive bibliographic research (104 references) has been done concerning the structure of Fak, its importance in tumor development, but also in other pathologies currently under study. The compounds currently subjected to clinical studies were therefore treated using the appropriate databases. Finally, the main chemical scaffolds currently under preclinical investigation were analyzed, focusing on their molecular structures and on the activity structure relationships (SAR)., Results: At the moment, only a few reversible ATP-competitive inhibitors are under investigation in pre-clinical studies and clinical trials. Other compounds, with different chemical scaffolds, are investigated to obtain more active and selective Fak inhibitors. This mini-review is a summary of different Fak functions in cancer and other pathologies; the compounds today in clinical trials and the recent chemical scaffolds (also included in patents) giving the most interesting results are investigated. In addition, PROTAC molecules are reported., Conclusion: All reported results evidenced that additional studies are necessary to design and synthesize new selective and more active compounds, although promising information has been obtained from associations between Fak inhibitors and other different anti- cancer drugs. In addition, the other important roles evidenced, both at the nuclear level and in non-cancerous cells, make this protein an increasingly important target in pharmaceutical chemistry., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea compounds (STIRUR 13, STIRUR 41 and BUR 12) have been demonstrated to exert a strong inhibitory effect on interleukin 8 or N-formyl-methionyl-leucyl-phenylalanine-induced chemotaxis of human neutrophils. Since the migration of cancer cells is comparable to that of neutrophils, the purpose of this study is to evaluate the biological effect of STIRUR 13, STIRUR 41 and BUR 12 on ACN and HTLA-230, two neuroblastoma (NB) cell lines with different degree of malignancy. HTLA-230 cells, stage-IV NB cells, have high plasticity and can serve as progenitors of endothelial cells. The results herein reported show that the three tested compounds were not cytotoxic for both NB cells and did not alter their clonogenic potential. However, all compounds were able to inhibit the ability of HTLA-230 to form vascular-like structures. On the basis of these findings, pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea derivatives could be proposed as agents potentially effective in counteracting NB malignancy by inhibiting cell migration and tumor angiogenesis which represent important hallmarks responsible for cancer survival and progression., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare.

The pyrazole nucleus has long been known as a privileged scaffold in the synthesis of biologically active compounds. Within the numerous pyrazole derivatives developed as potential drugs, this review is focused on molecules characterized by a urea function directly linked to the pyrazole nucleus in a different position. In the last 20 years, the interest of numerous researchers has been especially attracted by pyrazolyl-ureas showing a wide spectrum of biological activities, ranging from the antipathogenic activities (bacteria, plasmodium, toxoplasma, and others) to the anticarcinogenic activities. In particular, in the anticancer field, pyrazolyl-ureas have been shown to interact at the intracellular level on many pathways, in particular on different kinases such as Src, p38-MAPK, TrKa, and others. In addition, some of them evidenced an antiangiogenic potential that deserves to be explored. This review therefore summarizes all these biological data (from 2000 to date), including patented compounds.