185 research outputs found
Synthesis, SAR and molecular modelling studies of acylthiocarbamates and their parent thiocarbamates as potent non-nucleoside reverse transcriptase inhibitors related to PETT derivatives
No full text
Preparation and characterization of water-soluble, not PAMAM-structured dendrimer prodrugs of an anti-HIV-1 O-TC derivative for in vivo and clinical applications.
No full textAssessing the chemical cross-reaction from cefixime and some non-steroidal anti-inflammatory agents in a soluble formulation
No full textThe presence of chemical cross-reactivity betwen drugs may be an underestimated factor, responsible for decreased bio-availability of a drug active component(s); the absence of chemical cross-reactivity between drugs is undoubtedly the prerequisite for their simultaneous co-administration. Here, by means of thin layer chromatography, we show that cefixime, a third generation oral cephalosporin, does not display chemical reactivity versus a series of non-steroidal antiinflammatory agents. The four compounds tested can therefore be safely soluted together with the cephalosporin
Non-PAMAM amino acids-modified dendrimers nanoparticles for enhancing water-solubility of insoluble bioactive molecules: our state of the art
No full textNon-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, Università 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
HIGHLY-FUNCTIONALIZED AMINO PYRAZOLES AS ANTIOXIDANT AGENTS: A PRELIMINARY SYNTHETIC ACCESSIBILITY STUDY
No full text5-pyrazolyl urea derivatives showed interesting pharmaceutical properties. In particular, compounds 1
(Figure 1) showed promising antioxidant activity by inhibiting ROS formation in platelet. The free amino
group on the pyrazole ring appear to be essential for the antioxidant activity whereas the substitution of
the catechol moiety (X group, Figure 1) modulate the ability of the compound to block ROS formation. To further extend the SARs of derivatives 1 and evaluate the effect on the activity of the introduction of a
N-phenyl substituent on the pyrazole scaffold, we planned the synthesis of new amino pyrazoles 2 (Figure
1). In order to assess the chemical accessibility to the desired compounds, synthetic path A and B (Scheme
1) were considered. Methylhydrazine and p-anisaldehyde were selected as template reagents. Despite literature data, path A proved to be ineffective as the cyclization reaction could not occur in a
number of different experimental conditions. Path B led to the isolation of the desired compound as a
mixture of the two possible N-methyl isomers in good yields. In the poster, the different synthetic
conditions as well as the characterization of the obtained pyrazole isomers will be presented
Human rhinovirus 3C protease: a cysteine protease showing the trypsin(ogen)-like fold
No full textViral-encoded proteases cleave precursor polyprotein(s) leading to maturation of infectious virions. Strikingly, human rhinovirus 3C protease shows the trypsin(ogen)-like serine protease fold based on two topologically equivalent six-stranded beta-barrels, but displays residue Cys147 as the active site nucleophile. By contrast, papain, which is representative of most cysteine proteases, does not display the trypsin(ogen)-like fold. Remarkably, in human rhinovirus 3C cysteine protease, the catalytic residues Cys147, His40 and Glu71 are positioned as Ser195, His57 and Aspl02, respectively, building up the catalytic triad of serine proteases in the chymotrypsin-trypsin-elastase family. However, as compared to trypsin-like serine proteases and their zymogens, residue His40 and the oxyanion hole of human rhinovirus 3C cysteine protease, both key structural components of the active site, are located closer to the protein core. Human rhinovirus 3C cysteine protease cleaves preferentially Gln-Gly peptide bonds or, less commonly, the Gln-Ser, Gln-Ala, Glu-Ser or Glu-Gly pairs. Finally, human rhinovirus 3C cysteine protease and the 3CD cysteine proteasepolymerase covalent complex bind the 5‘ non-coding region of rhinovirus genomic RNA, an essential function for replication of the viral genome
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