In the context of our ongoing studies on chromane derivatives as inhibitors of the salicylate synthase from M. tuberculosis, we isolated a new, unexpected compound from the cyclization of ...3-(propargyloxy)-5-benzyloxy-benzoic acid methyl ester. Its molecular structure was elucidated by means of 1D and 2D NMR analyses, FT-IR, ESI-MS, and HRMS.
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Lysozyme (E.C. 3.2.1.17), an about 14 kDa protein and pI 11, widely spread in nature, is present in humans mainly in milk, saliva, and intestinal mucus as a part of innate defense mechanisms. It is ...endowed with antimicrobial activity due to its action as an N-acetylmuramidase, cleaving the 1-4β glycosidic linkage in the peptidoglycan layer of Gram-positive bacteria. This antimicrobial activity is exerted only against a limited number of Gram-negative bacteria. Different action mechanisms are proposed to explain its activity against Gram-negative bacteria, viruses, and fungi. The antiviral activity prompted the study of a possible application of lysozyme in the treatment of SARS-CoV-2 infections. Among the different sources of lysozyme, the chicken egg albumen was chosen, being the richest source of this protein (c-type lysozyme, 129 amino acids). Interestingly, the activity of lysozyme hydrochloride against SARS-CoV-2 was related to the heating (to about 100 °C) of this molecule. A chemical-physical characterization was required to investigate the possible modifications of native lysozyme hydrochloride by heat treatment. The FTIR analysis of the two preparations of lysozyme hydrochloride showed appreciable differences in the secondary structure of the two protein chains. HPLC and NMR analyses, as well as the enzymatic activity determination, did not show significant modifications.
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Topical application of the anti-inflammatory drug diclofenac (DCF) reduces the severity of systemic unwanted effects compared to its oral administration. A number of transdermal formulations are ...available on the market and routinely used in clinical and home-care settings. However, the amount of DCF delivered across the skin remains limited and often insufficient, thus making the oral route still necessary for achieving sufficient drug concentration at the inflamed site. In attempting to improve the transdermal penetration, we explored the combined use of DCF nanosuspensions with a microneedle roller. Firstly, DCF nanosuspensions were prepared by a top-down media milling method and characterized by spectroscopic, thermal and electron microscopy analyses. Secondly, the pore-forming action of microneedle rollers on skin specimens (ex vivo) was described by imaging at different scales. Finally, DCF nanosuspensions were applied on newborn pig skin (in vitro) in combination with microneedles roller treatment, assessing the DCF penetration and distribution in the different skin layers. The relative contribution of microneedle length, nanosuspension stabilizer and application sequence could be identified by systemically varying these parameters.
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Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of
(Mtb) have developed resistance ...against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of
and
, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (
-
), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (
), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound
offers promising prospects for future studies on the development of novel agents against mycobacterial infections.
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Curcumin has shown a potential extraordinary activity as an add-on ingredient in asthma treatment, due to its immunomodulatory and anti-inflammatory mechanism of action. However, its low water ...solubility and bioavailability lead to a poor therapeutic effect, which can be overcome by its formulation as nanocrystals. The aim of this study was to prepare a multicomponent formulation for the delivery of curcumin (CUR) and beclomethasone dipropionate (BDP) into the lungs as water-based nanosuspensions (NS). Single component formulations (CUR-NS, BDP-NS) and a multicomponent formulation (CUR+BDP-NS) were prepared through a wet ball media milling technique, using P188 as a non-toxic stabilizer. Characterization was carried out in terms of size, size distribution, zeta potential, nanocrystals morphology, and solid-state properties. Moreover, the inhalation delivery efficiency was studied with Next Generation Impactor (NGI, Apparatus E Ph. Eu). CUR-NS was optimized and showed a long-term stability and improved nanocrystals apparent solubility. The three formulations exhibited a nanocrystal mean diameter in the range of 200–240 nm and a homogenous particle size distribution. Aggregation or sedimentation phenomena were not observed in the multicomponent formulation on 90 days storage at room temperature. Finally, the nebulization tests of the three samples showed optimal aerodynamic parameters and MMAD < 5 µm.
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Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase ...MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of
in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (
), endowed with a promising activity against this enzyme (IC
= 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of
and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.
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Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed ...resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.
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Applying a formulation on the skin represents a patient-acceptable and therapeutically effective way to administer drugs locally and systemically. However, the stratum corneum stands as an ...impermeable barrier that only allows a very limited number of drugs to be distributed in the underlying tissues, limiting the feasibility of this administration route. Microneedle arrays are minimally invasive platforms that allow the delivery of drugs within/across the skin through the temporary mechanical disruption of the stratum corneum. In this work, microneedle arrays were combined with nanosuspensions, a technology for solubility enhancement of water insoluble molecules, for the skin delivery of diclofenac. Nanosuspensions were prepared using a top-down method and loaded in the tips of 500 µm or 800 µm high microneedles. The quality of the combined platform was assessed using electron microscopy and spectroscopic and calorimetry techniques, demonstrating the ability to load high amounts of the hydrophobic drug and the compatibility between excipients. Lastly, the application of nanosuspension-loaded microneedles on the skin in vitro allowed the delivery of diclofenac within and across the stratum corneum, proving the potential of this combination to enhance skin delivery of scarcely soluble drugs.
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Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new ...lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a K
i
of 8.8 µM and its antimycobacterial activity (MIC
99
= 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.
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Manakins are small suboscine passerines renowned for elaborate courtship displays and pronounced sexual dichromatism. We extracted and identified the carotenoid pigments found in the bright yellow to ...red feathers of 15 Neotropical manakin species. Rhodoxanthin (4′,5′-didehydro-4,5′-retro-β,β-carotene-3,3′-dione) of a deep red hue was widely found in the plumages of these birds. The 4-keto-carotenoids typically found in red plumages (α-doradexanthin, astaxanthin, canthaxanthin, etc.) were found in only the Flame-crested Manakin (Heterocercus linteatus) and the Red-headed Manakin (Pipra rubrocapilla). Rhodoxanthin was recently identified in the Pin-tailed Manakin (Ilicura militaris). Hudon et al. (2007) suggested that the Pin-tailed Manakin produces rhodoxanthin endogenously from dietary carotenoids, and this suggestion now finds some support in the pigment's wide and specific distribution in manakins. It is possible that this capacity arose in a common ancestor of manakins and cotingas, given that rhodoxanthin also occurs in the feathers of red cotingas (Phoenicircus spp.). Feathers with rhodoxanthin absorbed longer wavelengths of light than those with 4-ketocarotenoids, but not in Pipra, which has species with one or the other type of keto-carotenoids. We found that feathers with rhodoxanthin also contained ε,ε-caroten-3(3′)-ones (e.g., canary-xanthophyll B and the recently described piprixanthin), which are believed to be intermediates along the rhodoxanthin pathway. Manakins thus have the capability to produce a wide range of carotenoid pigments and bright yellow to red colors, on which natural and sexual selection may act.
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