Inhibitory interactions of the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold with Bunyavirales cap-snatching endonucleases expose relevant drug design features.

The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses.

ITC study on the interaction of some bile salts with tragacanth, Arabic, and guar gums with potential cholesterol-lowering ability.

Introduction: The urge of designing new safe and natural functional foods to control blood lipids and dispensable without the need of physician supervision, has increased especially after the coming into effect of the recent EU Commission regulation 2022/860, that regulates the consumption of "red yeast rice," made by fermentation of rice with , and perceived as a natural functional food, due to a health risk for frail consumers. The results of the present work are a part of the systematic study we are carrying out of the binding ability of some soluble dietary fibers (SDF) from different natural sources toward selected bile salts (BS).

Methods: Measurements were carried out by isothermal titration calorimetry (ITC) with the idea to shed light on the mechanism, if any, by which they show cholesterol-lowering activity.

Chemico-Physical Properties of Some 1,1'-Bis-alkyl-2,2'-hexane-1,6-diyl-bispyridinium Chlorides Hydrogenated and Partially Fluorinated for Gene Delivery.

The development of very efficient and safe non-viral vectors, constituted mainly by cationic lipids bearing multiple charges, is a landmark for in vivo gene-based medicine. To understand the effect of the hydrophobic chain's length, we here report the synthesis, and the chemico-physical and biological characterization, of a new term of the homologous series of hydrogenated bispyridinium surfactants, the 1,1'-bis-dodecyl-2,2'-hexane-1,6-diyl-bispyridinium chloride (GP12_6). Moreover, we have collected and compared the thermodynamic micellization parameters (cmc, changes in enthalpy, free energy, and entropy of micellization) obtained by isothermal titration calorimetry (ITC) experiments for hydrogenated surfactants GP12_6 and GP16_6, and for the partially fluorinated ones, FGP (where is the spacer length).

A potentiometric and spectrofluorimetric approach to unravel inhibitory effects of semi- and thiosemicarbazones on mushroom tyrosinase activity.

The inhibitory effects on mushrooms tyrosinase activity of some semi- and thiosemicarbazones were investigated. While the semicarbazones are inactive, the thiosemicarbazones are, in general, more active than the reference (kojic acid, IC = 70 μM), with maximum activity obtained with benzaldehyde thiosemicarbazone (IC = 7 μM). These inhibitors probably act by coordination of the copper(II) metal ions in the active site of tyrosinase: effectively, potentiometric studies conducted in water solutions confirm that the most active thiosemicarbazone is a good ligand for copper(II) ions.

On the mechanism of the cholesterol lowering ability of soluble dietary fibers: Interaction of some bile salts with pectin, alginate, and chitosan studied by isothermal titration calorimetry.

Reducing high blood cholesterol is an important strategy to decrease the chances of a cardiovascular disease occurrence, the main cause of mortality in western developed countries. Therefore, the search for an alternative therapeutic or preventive approach being natural, biocompatible, and not toxic is still more relevant than ever. This need is particularly felt in Pediatrics for treating childhood hypercholesterolemia, due to statins interference in the production of steroid hormones in prepuberal children.

Human Serine Racemase Weakly Binds the Third PDZ Domain of PSD-95.

Human serine racemase (hSR) is a pyridoxal-5'-phosphate (PLP)-dependent dimer that catalyzes the formation of D-serine from L-serine, as well as the dehydration of both L- and D-serine to pyruvate and ammonia. As D-serine is a co-agonist of N-methyl-D-aspartate receptors (NMDARs), hSR is a key enzyme in glutamatergic neurotransmission. hSR activity is finely regulated by Mg, ATP, post-translational modifications, and the interaction with protein partners.

Gene-Delivery Ability of New Hydrogenated and Partially Fluorinated Surfactants with Six Methylene Spacers.

The pandemic emergency determined by the spreading worldwide of the SARS-CoV-2 virus has focused the scientific and economic efforts of the pharmaceutical industry and governments on the possibility to fight the virus by genetic immunization. The genetic material must be delivered inside the cells by means of vectors. Due to the risk of adverse or immunogenic reaction or replication connected with the more efficient viral vectors, non-viral vectors are in many cases considered as a preferred strategy for gene delivery into eukaryotic cells.

Statistical Inference for Ergodic Algorithmic Model (EAM), Applied to Hydrophobic Hydration Processes.

The thermodynamic properties of hydrophobic hydration processes can be represented in probability space by a Dual-Structure Partition Function {} = {M} · {}, which is the product of a Motive Partition Function {M} multiplied by a Thermal Partition Function {}. By development of {}, parabolic binding potential functions α) ln = (-Δ) ={1/))} and β) ln = (-Δ) = {)()} have been calculated. The resulting binding functions are "" functions dependent on the reciprocal interactions between the primary function 1/) or ) with the secondary function ) or (), respectively.

Hydrophobic Hydration Processes: Intensity Entropy and Null Thermal Free Energy and Density Entropy and Motive Free Energy.

The processes at the molecule level, which are the source of the ergodic properties of thermodynamic systems, are analyzed with special reference to entropy. The entropy change produced by increasing the temperature depends on the increase of velocity of the particles with a decrease of the squared mean sojourn time (τ ) and gradual loss of instant energy intensity. The diminution, which is due to dilution, of the number of terms in the summation of cumulative sojourn time (τ ) produces loss of energy density, thus generating a gradual increase of density entropy, d .

Hydroxyphenyl thiosemicarbazones as inhibitors of mushroom tyrosinase and antibrowning agents.

Tyrosinase is a metalloenzyme involved in o-hydroxylation of monophenols and oxidation of o-diphenols to o-quinones, with formation of brown or black pigments (melanines). Tyrosinase inhibitors are of great interest in medicine and cosmetics (skin whitening compounds), but also in food and beverage industry (antibrowning agents). Here we report on the activity as mushroom tyrosinase inhibitors of a series of hydroxyphenyl thiosemicarbazones (1-5): one of them revealed an inhibitory activity stronger than kojic acid, used as reference.

Hydrophobic Hydration Processes. I: Dual-Structure Partition Function for Biphasic Aqueous Systems.

The thermodynamic properties of hydrophobic hydration processes have been analyzed and assessed. The thermodynamic binding functions result to be related to each other by the mathematical relationships of an ergodic algorithmic model (EAM). The active dilution of species A in solution is expressed as = 1/(Φ· ) with thermal factor Φ = and (1/ ) = , where = ideal dilution.

Antiviral activity and metal ion-binding properties of some 2-hydroxy-3-methoxyphenyl acylhydrazones.

Here we report on the results obtained from an antiviral screening, including herpes simplex virus, vaccinia virus, vesicular stomatitis virus, Coxsackie B4 virus or respiratory syncytial virus, parainfluenza-3 virus, reovirus-1 and Punta Toro virus, of three 2-hydroxy-3-methoxyphenyl acylhydrazone compounds in three cell lines (i.e. human embryonic lung fibroblast cells, human cervix carcinoma cells, and African Green monkey kidney cells).

Nonviral gene-delivery by highly fluorinated gemini bispyridinium surfactant-based DNA nanoparticles.

Biological and thermodynamic properties of a new homologous series of highly fluorinated bispyridinium cationic gemini surfactants, differing in the length of the spacer bridging the pyridinium polar heads in 1,1' position, are reported for the first time. Interestingly, gene delivery ability is closely associated with the spacer length due to a structural change of the molecule in solution. This conformation change is allowed when the spacer reaches the right length, and it is suggested by the trends of the apparent and partial molar enthalpies vs molality.

A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents.

Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II).

Synthesis, Physicochemical Characterization, and Interaction with DNA of Long-Alkyl-Chain Gemini Pyridinium Surfactants.

Pyridinium gemini surfactants with hexadecyl chains linked to nitrogen atoms and a tuned aliphatic spacer that bridges the two pyridinium polar heads in 2,2'-positions have been synthesized and characterized. A multitechnique approach allowed us to study the aggregation behavior, using conductivity, surface tension, and fluorescence. Graphs of the specific conductivity (κ) versus the surfactant molar concentration (C), and graphs of the molar conductivity (Λ) versus C suggest pre-aggregation phenomena of these amphiphiles at very low concentration.

Nonviral gene delivery: gemini bispyridinium surfactant-based DNA nanoparticles.

The interaction with a model membrane, the formation of DNA nanoparticles, and the transfection ability of a homologous series of bispyridinium dihexadecyl cationic gemini surfactants, differing in the length of the alkyl spacer bridging the two pyridinium polar heads in the 1 and 1' positions (P16-n with n = 3, 4, 8, 12), have been studied by means of differential scanning calorimetry (DSC), atomic force microscopy, electrophoresis mobility shift assay, and transient transfection assay measurements. The results presented here show that their performance in gene delivery is strictly related to their structure in solution. For the first time the different transfection activities of the compounds can be explained by referring to their thermodynamic properties in solution, previously studied.

Antiretroviral activity of metal-chelating HIV-1 integrase inhibitors.

Data regarding the activity of metal complexes against HIV virus in cell are surprisingly scarce. In this study, we present the antiviral activity against HIV-infected cells of different types of chelating ligands and of their metal complexes. In particular, the carboxamide chelating scaffold and the corresponding coordination compounds demonstrated an interesting antiviral profile in the nanomolar range.

Diketoacid chelating ligands as dual inhibitors of HIV-1 integration process.

HIV-1 Integrase (IN) represents a very attractive pharmacological target for the development of new and more efficient drugs. Recently, an allosteric inhibitory approach also emerged, that targets the interaction between IN and cellular cofactors, such as LEDGF/p75. Small molecules based on the diketoacid pharmachophore were studied for their ability to inhibit at the same time integration and IN-LEDGF/p75 interaction (dual inhibitors): in this study, we evaluated three indole diketoacid derivatives and their magnesium(II) complexes for their ability to act as dual inhibitors.

Metal-chelating 2-hydroxyphenyl amide pharmacophore for inhibition of influenza virus endonuclease.

The influenza virus PA endonuclease is an attractive target for development of novel anti-influenza virus therapeutics. Reported PA inhibitors chelate the divalent metal ion(s) in the enzyme's catalytic site, which is located in the N-terminal part of PA (PA-Nter). In this work, a series of 2-hydroxybenzamide-based compounds have been synthesized and biologically evaluated in order to identify the essential pharmacophoric motif, which could be involved in functional sequestration of the metal ions (probably Mg(2+)) in the catalytic site of PA.

Investigating the role of metal chelation in HIV-1 integrase strand transfer inhibitors.

HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir.

Hydrophobic hydration processes thermal and chemical denaturation of proteins.

The hydrophobic hydration processes have been analysed under the light of a mixture model of water that is assumed to be composed by clusters (W(5))(I), clusters (W(4))(II) and free water molecules W(III). The hydrophobic hydration processes can be subdivided into two Classes A and B. In the processes of Class A, the transformation A(-ξ(w)W(I)→ξ(w)W(II)+ξ(w)W(III)+cavity) takes place, with expulsion from the bulk of ξ(w) water molecules W(III), whereas in the processes of Class B the opposite transformation B(-ξ(w)W(III)-ξ(w)W(II)→ξ(w)W(I)-cavity) takes place, with condensation into the bulk of ξ(w) water molecules W(III).

HIV-1 IN strand transfer chelating inhibitors: a focus on metal binding.

Most active and selective strand transfer HIV-1 integrase (IN) inhibitors contain chelating functional groups that are crucial feature for the inhibition of the catalytic activities of the enzyme. In particular, diketo acids and their derivatives can coordinate one or two metal ions within the catalytic core of the enzyme. The present work is intended as a contribution to elucidate the mechanism of action of the HIV-IN inhibitors by studying the coordinative features of H₂L¹ (L-708,906), an important member of the diketo acids family of inhibitors, and H₂L₂, a model for S-1360, another potent IN inhibitor.

Hydrophobic hydration processes. General thermodynamic model by thermal equivalent dilution determinations.

The "hydrophobic hydration processes" can be satisfactorily interpreted on the basis of a common molecular model for water, consisting of two types of clusters, namely W(I) and W(II) accompanied by free molecules W(III). The principle of thermal equivalent dilution (TED) is the potent tool (Ergodic Hypothesis) employed to monitor the water equilibrium and to determine the number xi(w) of water molecules W(III) involved in each process. The hydrophobic hydration processes can be subdivided into two Classes: Class A includes those processes for which the transformation A(-xi(w)W(I)-->xi(w)W(II)+xi(w)W(III)+cavity) takes place with the formation of a cavity, by expulsion of xi(w) water molecules W(III) whereas Class B includes those processes for which the opposite transformation B(-xi(w)W(II)-xi(w)W(III)-->xi(w)W(I)-cavity) takes place with reduction of the cavity, by condensation of xi(w) water molecules W(III).

Synthesis and properties of cationic surfactants with tuned hydrophylicity.

A series of pyridinium-based cationic surfactants has been synthesised and their amphiphilic properties have been studied by conductivity and surface tension measurements. The modification of the substitution pattern on the pyridinium ring by hydrophobic moieties (methyl vs. hydrogen and presence or not of condensed benzene ring) gave the opportunity to investigate structure-activity relationships.

From ligand to complexes. Part 2. Remarks on human immunodeficiency virus type 1 integrase inhibition by beta-diketo acid metal complexes.

Previously, we synthesized a series of beta-diketo acid metal complexes as novel HIV-1 integrase (IN) inhibitors (J. Med. Chem.