Mono- and di-acylated imidazolidine-2-thione derivatives: synthesis, cytotoxicity evaluation and computational studies

Imidazolidine-2-thione substructure represents a pharmaceutically attractive scaffold, being included in different antimicro- bial, 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 thio- urea 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

Regioselective Synthesis, Structural Characterization, and Antiproliferative Activity of Novel Tetra-Substituted Phenylaminopyrazole Derivatives

A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3 and 4 of the pyrazole ring, was prepared by the one pot condensation of active methylene reagents, phenylisothiocyanate and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Fur-thermore, the evaluation of alternative stepwise protocols affected the chemo- and re-gio-selectivity outcome of the one-pot procedure. The chemical identity of two N-methyl pyrazole isomers, selected as prototypes of the whole series, was unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behaviour of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials

Characterization data of water-soluble hydrophilic and amphiphilic dendrimers prodrugs for delivering bioactive chemical entities otherwise non soluble.

More than 40% of bioactive chemical entities (BCEs) developed in pharmaceutical industry are almost water-insoluble, poorly orally bioavailable and/or not via parenteral administrable, and this strongly limits their clinical applications. Drug Delivery (DD) is an engineered technology dealing with the development of delivery systems (DDSs) able to solubilize, transport, target release and maintain therapeutic drugs concentration where needed for long periods. DD frequently makes use of nanosized carriers, often positive charged, including dendrimer such as commercially available and strongly cationic PAMAM and PEI. Nowadays, uncharged dendrimer scaffolds modified with amino acids-modified in their cationic form, are preferred because a more controlled number of nitrogen atoms causes less damage to cells. Then, two hydrophilic (1, 2) [1] (Fig. 1) and three amphiphilic (3-5) [2] (Fig. 2) water-soluble dendrimers were prepared and completely characterized. Once established through proper routine investigations, that these materials could work well as DDSs, they have been used to physically entrap two completely insoluble BCEs i.e. the thiocarbamate (O-TC) 6 [3] and Ellagic Acid (EA) 7 (Fig. 3) with the aim at improving their solubility and in parallel at protecting them from early degradation, at promoting their fast cellular up-take and thus reducing eventual systemic toxicity. Without resorting to toxic excipients and harmful solubilizing agents often used despite the resulting unpleasant side effects, five structurally different nanodispersions (DPXs) loaded with 6 [4] and two with 7 [5] were achieved and completely characterized to confirm their structure and to evaluate their potentiality in biomedical applications

Non-PAMAM amino acids-modified dendrimers nanoparticles for enhancing water-solubility of insoluble bioactive molecules: our state of the art

Non-PAMAM amino acids-modified dendrimers nanoparticles for enhancing water-solubility of insoluble bioactive molecules: our state of the art Silvana Alfei,* Andrea Spallarossa, Silvia Catena, Federica Turrini, Guendalina Zuccari, Anna Pittaluga, Raffaella Boggia Dipartimento di Farmacia, Universit\ue0 di Genova, Viale Cembrano 4, I-16148 Genova, Italy E-mail: [email protected] ABSTRACT Water-solubility is essential for GIT absorbability or parenteral administration of drugs, therefore it is a key parameter to achieve the systemic drug concentration necessary for an effective therapeutic activity. Unfortunately, low aqueous solubility is the major problem with bioactive chemical entities (BCEs), in fact, more than 40% BCEs developed in pharmaceutical industry are practically water-insoluble. As a consequence, great are the research efforts focused on the development of new techniques aiming at enhancing it. Toxic excipients and harmful solubilizing agents were also extensively used for solubilizing and delivering non water-soluble drugs, despite the resulting unpleasant side effects complained of by patients. Nowadays, safer strategies, such as drugs physicochemical modifications or particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant and complexation are being exploited. As far as what regards dispersion/complexation techniques, nanoparticles, including dendrimers, are intensely utilized for this purpose, thus in parallel achieving drugs protection from early degradation, more efficient target delivery into cells and tissues and lower systemic toxicity. Synthetic thiocarbamate (O-TC 1) (Fig. 1) is a non-nucleoside HIV-1 reverse transcriptase inhibitor [1] while Ellagic Acid (EA 2) (Fig. 2) is a polyphenol present in some fruits, nuts and seeds endowed with strong antioxidant, anti-inflammatory and other several healthy properties. Unfortunately, both of them are practically insoluble (Table 1), non orally bioavailable, non parenteral administrable, then non usable for therapeutic purposes in their free forms. Fig. 1: Structure of O-TC 1 Fig. 2: Structure of EA 2 Fig. 3: Examples of hydrophilic (left) and amphiphilic (right) dendrimers structure During the last year, these problems have been addressed and successfully resolved by us, and in this communication, the reached promising outcomes have been summarized and the current state of the art provided. Afar from commercially high cytotoxic PAMAM, five non cells-damaging amino acid-modified hydrophilic (3, 4) [2] and amphiphilic (5-7) [3] dendrimers (Fig. 3) have been synthetized and then used as polymer nano-containers to improve 1 and 2 water-solubility. Five (8-12) [4] and two (13, 14) [5] structurally different drugs-loaded nanodispersions (DPXs) were obtained respectively. The structures were confirmed by FT-IR and NMR analysis and all the samples have resulted in being endowed with very good Drug Loading (DL %). Compound 1, totally insoluble except for in highly diluted DMSO when free, once entrapped in dendrimers, shown to be well soluble both in water and in ethanol. In the case of 2, water-solubility was increased even up to 1000 times compared to the free form. For the prerogatives demonstrated in the performed routine analyses, the prepared DPXs could be considered eligible for biomedical and therapeutic applications thus allowing to exploit 1 and 2 pharmacological properties. REFERENCES: 1. A. Spallarossa et al., Eur. J. Med. Chem., 44, 2190 (2009). 2. S. Alfei & S. Catena, Polym. Advan. Technol., 29, 2735 (2018). 3. S. Alfei & S. Catena, Polym. Int., 67, 1572 (2018). 3. S. Alfei et al., Eur. J. Pharm. Sci., 124, 153 (2018). 4. S. Alfei et al., New J. Chem., 2019, DOI: 10.1039/c8nj05657a

Potent and Broad-Spectrum Bactericidal Activity of a Nanotechnologically Manipulated Novel Pyrazole

: The antimicrobial potency of the pyrazole nucleus is widely reported these days, and pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against multidrug-resistant (MDR) bacteria. Consequently, 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), recently reported as a weak antiproliferative agent, was considered to this end. To overcome the CR232 water solubility issue and allow for the determination of reliable minimum inhibitory concentration values (MICs), we initially prepared water-soluble and clinically applicable CR232-loaded nanoparticles (CR232-G5K NPs), as previously reported. Here, CR232-G5K NPs have been tested on several clinically isolates of Gram-positive and Gram-negative species, including MDR strains. While for CR232 MICs 65 128 \ub5g/mL (376.8 \ub5M) were obtained, very low MICs (0.36-2.89 \ub5M) were observed for CR232-G5K NPs against all of the considered isolates, including colistin-resistant isolates of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 \ub5M). Additionally, in time-kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all isolates tested, regardless of their difficult-to-treat resistance. Conjecturing a clinical use of CR232-G5K NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favorable selectivity indices. Collectively, due to its physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by broad spectrum MDR bacteria

Iterative design and optimization of initially inactive Proteolysis Targeting Chimeras (PROTACs) identify VZ185 as a potent, fast and selective von Hippel-Lindau (VHL)-based dual degrader probe of BRD9 and BRD7

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers, and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown, and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations

A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility

Purpose: To verify the capability of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. Methods: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin\u2019s disease (DXR dose: 40\u201350 mg/m2 per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. Results: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. Conclusions: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting

Amino-Pyrazoles in Medicinal Chemistry: A Review

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