Monte Carlo Method and GA-MLR-Based QSAR Modeling of NS5A Inhibitors against the Hepatitis C Virus.

Hepatitis C virus (HCV) is a serious disease that threatens human health. Despite consistent efforts to inhibit the virus, it has infected more than 58 million people, with 300,000 deaths per year. The HCV nonstructural protein NS5A plays a critical role in the viral life cycle, as it is a major contributor to the viral replication and assembly processes. Therefore, its importance is evident in all currently approved HCV combination treatments. The present study identifies new potential compounds for possible medical use against HCV using the quantitative structure-activity relationship (QSAR). In this context, a set of 36 NS5A inhibitors was used to build QSAR models using genetic algorithm multiple linear regression (GA-MLR) and Monte Carlo optimization and were implemented in the software CORAL. The Monte Carlo method was used to build QSAR models using SMILES-based optimal descriptors. Four splits were performed and 24 QSAR models were developed and verified through internal and external validation. The model created for split 3 produced a higher value of the determination coefficients using the validation set (R2 = 0.991 and Q2 = 0.943). In addition, this model provides interesting information about the structural features responsible for the increase and decrease of inhibitory activity, which were used to develop eight novel NS5A inhibitors. The constructed GA-MLR model with satisfactory statistical parameters (R2 = 0.915 and Q2 = 0.941) confirmed the predicted inhibitory activity for these compounds. The Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) predictions showed that the newly designed compounds were nontoxic and exhibited acceptable pharmacological properties. These results could accelerate the process of discovering new drugs against HCV.

COVID-19: In silico identification of potent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2.

The COVID-19 has been creating a global crisis, causing countless deaths and unbearable panic. Despite the progress made in the development of the vaccine, there is an urge need for the discovery of antivirals that may better work at different stages of SARS-CoV-2 reproduction. The main protease (Mpro) of the SARS-CoV-2 is a crucial therapeutic target due to its critical function in virus replication. The α-ketoamide derivatives represent an important class of inhibitors against the Mpro of the SARS-CoV. While there is 99% sequence similarity between SARS-CoV and SARS-CoV-2 main proteases, anti-SARS-CoV compounds may have a huge demonstration's prospect of their effectiveness against the SARS-CoV-2. In this study, we applied various computational approaches to investigate the inhibition potency of novel designed α-ketoamide-based compounds. In this regard, a set of 21 α-ketoamides was employed to construct a QSAR model, using the genetic algorithm-multiple linear regression (GA-MLR), as well as a pharmacophore fit model. Based on the GA-MLR model, 713 new designed molecules were reduced to 150 promising hits, which were later subject to the established pharmacophore fit model. Among the 150 compounds, the best selected compounds (3 hits) with greater pharmacophore fit score were further studied via molecular docking, molecular dynamic simulations along with the Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Our approach revealed that the three hit compounds could serve as potential inhibitors against the SARS-CoV-2 Mpro target.

Dependence of the interaction mechanisms between L-serine and O-phospho-L-serine with calcium hydroxyapatite and copper modified hydroxyapatite in relation with the acidity of aqueous medium.

Motivated by the role of copper ions in biological processes the aim of this study was to elucidate the impact of copper ions bound to hydroxyapatite on L-serine (L-Ser) and O-phospho-L-serine (O-Ph-L-Ser) adsorption at different acidity of aqueous solutions. The adsorption phenomenon was studied by FTIR, UV, and AA spectroscopy, XRD and thermal analysis methods together with the evolved gases analysis taking into consideration the ionic state of the amino acids as well as the apatite surface state, which are tightly correlated with the solution pH. In acidic solution, the main process involves apatite dissolution releasing calcium and copper ions. At pH > 5 the complexation of amino acids with Ca2+ or Cu2+ ions is more important leading also to the release of cations. The ability of copper ions to form water soluble complexes with L-Ser and O-Ph-L-Ser leads to an important loss of these ions, while calcium release is very low at this pH. Therefore, the use of copper ions substituting calcium in the apatite structure to enhance the ability of amino acids adsorption on the apatite surface seems problematic even at pH > 5.

New unsymmetrically benzene-fused bis (tetrathiafulvalene): synthesis, characterization, electrochemical properties and electrical conductivity of their materials.

The synthesis of new unsymmetrically benzene-fused bis (tetrathiafulvalene) has been carried out by a cross-coupling reaction of the respective 4,5-dialkyl-1,3-dithiole-2-selenone 6-9 with 2-(4-(p-nitrophenyl)-1,3-dithiole-2-ylidene)-1,3,5,7-tetrathia-s-indacene-6-one 5 prepared by olefination of 4-(p-nitrophenyl)-1,3-dithiole-2-selenone 3 and 1,3,5,7-tetrathia-s-indacene-2,6-dione 4. The conversion of the nitro moiety 10a-d to amino 11a-d then dibenzylamine 12a-d groups respectively used reduction and alkylation methods. The electron donor ability of these new compounds has been measured by cyclic voltammetry (CV) technique. Charge transfer complexes with tetracyanoquino-dimethane (TCNQ) were prepared by chemical redox reactions. The complexes have been proven to give conducting materials.

Structural variability in multifunctional metal xylenediaminetetraphosphonate hybrids.

Two new families of divalent metal hybrid derivatives from the aromatic tetraphosphonic acids 1,4- and 1,3-bis(aminomethyl)benzene-N,N'-bis(methylenephosphonic acid), (H2O3PCH2)2-N-CH2C6H4CH2-N(CH2PO3H2)2 (designated herein as p-H8L and m-H8L) have been synthesized by crystallization at room temperature and hydrothermal conditions. The crystal structures of M[(HO3PCH2)2N(H)CH2C6H4CH2N(H)(CH2PO3H)2(H2O)2]·2H2O (M = Mg, Co, and Zn), M-(p-H6L), and M[(HO3PCH2)2N(H)CH2C6H4CH2N(H)(CH2PO3H)2]·nH2O (M = Ca, Mg, Co, and Zn and n = 1-1.5), M-(m-H6L), were solved ab initio by synchrotron powder diffraction data using the direct methods and subsequently refined using the Rietveld method. The crystal structure of the isostructural M-(p-H6L) is constituted by organic-inorganic monodimensional chains where the phosphonate moiety acts as a bidentate chelating ligand bridging two metal octahedra. M-(m-H6L) compounds exhibit a 3D pillared open-framework with small 1D channels filled with water molecules. These channels are formed by the pillaring action of the organic ligand connecting adjacent layers through the phosphonate oxygens. Thermogravimetric and X-ray thermodiffraction analyses of M-(p-H6L) showed that the integrity of their crystalline structures is maintained up to 470 K, without significant reduction of water content, while thermal decomposition takes place above 580 K. The utility of M-(p-H6L) (M = Mg and Zn) hybrid materials in corrosion protection was investigated in acidic aqueous solutions. In addition, the impedance data indicate both families of compounds display similar proton conductivities (σ ∼ 9.4 × 10(-5) S·cm(-1), at 98% RH and 297 K), although different proton transfer mechanisms are involved.

New coumarin derivatives accessible in short and eco-friendly conditions with antifungal activity.

Aim: The synthesis of a novel class of compounds bearing a coumarin entity was targeted. They are either iminocoumarins or characterized by the presence of a pyridone ring fused within the iminocoumarin scaffold. Methods & results: The targeted compounds were synthesized through a short method, thanks to microwave activation. The study evaluated the antifungal activity of 13 newly synthesized compounds against a new fungal strain of Aspergillus niger. The most active compound showed activity comparable to the widely used reference drug, amphotericin B. Conclusion: The conditions and the ease of synthesis warrant high potential of the method for diversity-oriented synthesis, very useful within the drug discovery area.

Assessment of the anti-inflammatory and analgesic effects of Opuntia ficus indica L. Cladodes extract.

This study aimed to evaluate the anti-inflammatory and analgesic properties of the methanolic extract of Opuntia ficus indica L. in small animal (rats and mice model). The current treatment for febrile conditions often involves the use of non-steroidal anti-inflammatory drugs (NSAIDs), which can have adverse effects, particularly gastrointestinal ulcers. Therefore, there is a growing need to explore natural alternatives with fewer side effects. The study utilized various experimental models to assess the effects of the extract. The results demonstrated a significant analgesic effect of the extract, as evidenced by a reduction in pain induced by acetic acid and hot plate tests. Additionally, the extract exhibited anti-inflammatory effects, as indicated by a decrease in carrageenan-induced paw edema and dextran-induced inflammation. To gain insights into the chemical composition of the extract, HPLC analysis was conducted. The analysis successfully identified and quantified 20 compounds, including luteolin, galangin, catechin, thymol, methylated quercetin, quercetin, rutin, acacetin, hesperidin, apigenin, kaempferol, pinocembrin, chrysin, gallic acid, caffeic acid, ascorbic acid, ferulic acid, m-coumaric acid, rosmarinic acid, and trans-cinnamic acid.The findings suggest that Opuntia ficus indica L. extract holds promise as an effective and reasonably priced natural remedy for pain and inflammation in rats and mice model. The comprehensive chemical composition analysis provided valuable insights into the presence of various bioactive compounds, which may contribute to the observed therapeutic effects. Further research and exploration of the extract's mechanisms of action are warranted to fully understand its potential in small animal healthcare.

Effect of isopropyl side chain branching and different anions on electronic structure, vibrational spectra, and hydrogen bonding of isopropyl-imidazolium-based ionic liquids: Experimental and theoretical investigations.

In the present work, four branched methylated, 1,2-dimethyl-3-isopropyl-imidazolium (i-[C3Dmim+]) and protonated,1-methyl-3-isopropyl-imidazolium (i-[C3mim+])-based ionic liquids (ILs) with varying anion (Br-, BF4-, PF6-, and NTf2-) were synthesized and investigated by NMR, infrared (IR) and Raman spectroscopy. Based on infrared and Raman spectroscopy, complete vibrational assignments have been performed. The IR and Raman analysis revealed that the vibrational spectra are virtually unaffected upon methylation, while significant frequency changes were observed by changing anion. Furthermore, to determine the electronic structure, energetic stability, and vibrational properties of these i-[C3Dmim]Y, i-[C3mim]Y (Y = Br, BF4, PF6, and NTf2) ion pairs, quantum chemical calculations including the dispersion correction method are performed both on single ions and on ionic couples. The calculated electron density was analyzed to expose non-covalent intra- and interionic interactions by the quantum theory of atoms in molecules (AIM) and interpreted in terms of both anion dependence and type of interaction. Computational results suggest that for all ionic couples the most energetically stable configuration is obtained with the anions located close to the C2 position of the imidazolium cation. However, in the case of i-[C3mim]NTf2 and i-[C3Dmim]BF4, similar energies were obtained in configurations 2 and 3 where the anion is located above the imidazolium ring. For i-[C3mim]Br a stronger hydrogen bond is predicted than for other studied ILs. Calculations indicate that a red shift of the CH stretching bands should occur due to hydrogen bonding; indeed, such displacement of bands is experimentally observed.

High proton conductivity in a flexible, cross-linked, ultramicroporous magnesium tetraphosphonate hybrid framework.

Multifunctional materials, especially those combining two or more properties of interest, are attracting immense attention due to their potential applications. MOFs, metal organic frameworks, can be regarded as multifunctional materials if they show another useful property in addition to the adsorption behavior. Here, we report a new multifunctional light hybrid, MgH(6)ODTMP·2H(2)O(DMF)(0.5) (1), which has been synthesized using the tetraphosphonic acid H(8)ODTMP, octamethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid), by high-throughput methodology. Its crystal structure, solved by Patterson-function direct methods from synchrotron powder X-ray diffraction, was characterized by a 3D pillared open framework containing cross-linked 1D channels filled with water and DMF. Upon H(2)O and DMF removal and subsequent rehydration, MgH(6)ODTMP·2H(2)O (2) and MgH(6)ODTMP·6H(2)O (3) can be formed. These processes take place through crystalline-quasi-amorphous-crystalline transformations, during which the integrity of the framework is maintained. A water adsorption study, at constant temperature, showed that this magnesium tetraphosphonate hybrid reversibly equilibrates its lattice water content as a function of the water partial pressure. Combination of the structural study and gas adsorption characterization (N(2), CO(2), and CH(4)) indicates an ultramicroporous framework. High-pressure CO(2) adsorption data are also reported. Finally, impedance data indicates that 3 has high proton conductivity σ = 1.6 × 10(-3) S cm(-1) at T = 292 K at ~100% relative humidity with an activation energy of 0.31 eV.

Synthesis and electrochemical proprieties of novel unsymmetrical bis-tetrathiafulvalenes and electrical conductivity of their charge transfer complexes with tetracyanoquinodimethane (TCNQ).

The synthesis and properties of a series of bis-tetrathiafulvalenes (bis-TTFs) containing nitrophenyl, aminophenyl or dimethylaminophenyl is reported. The synthesis was carried out by using routes involving Wittig-type, cross-coupling, reduction and alkylation reactions. The electron donor ability of these new compounds has been measured by cyclic voltammetry (CV). Charge transfer complexes with tetracyanoquinodimethane (TCNQ) were prepared by chemical redox reactions. The complexes have been proven to give conducting materials.

A computational study of the inclusion of ß-cyclodextrin and nicotinic acid: DFT, DFT-D, NPA, NBO, QTAIM, and NCI-RDG studies.

Forming complexes with cyclodextrins can protect nicotinic acid (vitamin B3) from premature metabolism and enhance the solubility and stability of this drug. In this work, the formation of the inclusion complex of the neutral form of nicotinic acid and ß-cyclodextrin was achieved. The complex is modeled using PM3, PM6-D4H3, and PM7, by considering two orientations of the guest: A and B, one is from wide to narrow rim, and the second is from narrow to the wide rim, respectively. The global minima positions were re-optimized using three density function methods: MN-15, B3LYP, and PW6B95-D3 with polarized Pople basis set 6-31G(d) in gas and aqueous phase. Orientation A showed the minimum complexation energy where the carboxylic functional group of nicotinic acid is located on the primary hydroxyl rim of ß-cyclodextrin and the pyridine ring is totally embedded in the cavity. To further our study on the nature of complexation and the interactions of this host-guest system, different calculations were done. The reactivity indices showed that orientation A is harder than B and more electrophilic; the charge transfer occurred from the host to the guest and was confirmed by the natural population analysis (NPA). The natural bond orbitals (NBO) reveal the delocalization of orbitals between the host and the guest, quantum theory of atoms in molecules (QTAIM) analysis, and non-covalent interaction (NCI) analysis based on a reduced density gradient (RDG) give a detailed description of the nature of interactions between the host and the guest such as the hydrogen bonding and van der Waals interaction, and confirmed the stability of the complex given by the orientation A.

In silico design and analysis of NS4B inhibitors against hepatitis C virus.

The hepatitis C virus is a communicable disease that gradually harms the liver leading to cirrhosis and hepatocellular carcinoma. Important therapeutic interventions have been reached since the discovery of the disease. However, its resurgence urges the need for new approaches against this malady. The NS4B receptor is one of the important proteins for Hepatitis C Virus RNA replication that acts by mediating different viral properties. In this work, we opt to explore the relationships between the molecular structures of biologically tested NS4B inhibitors and their corresponding inhibitory activities to assist the design of novel and potent NS4B inhibitors. For that, a set of 115 indol-2-ylpyridine-3-sulfonamides (IPSA) compounds with inhibitory activity against NS4B is used. A hybrid genetic algorithm combined with multiple linear regressions (GA-MLR) was implemented to construct a predictive model. This model was further used and applied to a set of compounds that were generated based on a pharmacophore modeling study combined with virtual screening to identify structurally similar lead compounds. Multiple filtrations were implemented for selecting potent hits. The selected hits exhibited advantageous molecular features, allowing for favorable inhibitory activity against HCV. The results showed that 7 out of 1285 screened compounds, were selected as potent candidate hits where Zinc14822482 exhibits the best predicted potency and pharmacophore features. The predictive pharmacokinetic analysis further justified the compounds as potential hit molecules, prompting their recommendation for a confirmatory biological evaluation. We believe that our strategy could help in the design and screening of potential inhibitors in drug discovery.Communicated by Ramaswamy H. Sarma.

Thermal Decomposition, Low Temperature Phase Transitions and Vapor Pressure of Less Common Ionic Liquids Based on the Bis(trifuoromethanesulfonyl)imide Anion.

Four ionic liquids (ILs) based on the bis(trifluoromethanesulfonyl)imide (NTf2) anion were synthesized and characterized concerning their thermal stability, the occurrence of low temperature phase transitions and their volatility. All these physical quantities are highly important for possible applications. Both monocationic and dicationic ILs were considered. All ILs exhibit thermal stability exceeding 350 °C, an extremely high value, due to the presence of the NTf2 anion. Monocationic ILs can undergo crystallization, and they melt at 1 and 38 °C. On the contrary, dicationic ILs containing large positively charged ions display only a glass transition around -40 °C, without any crystallization or melting process; this fact is particularly important in view of the possibly low temperature applications of the dication ILs. The vapor pressure, pv, of the four ILs was measured by isothermal thermogravimetry in the temperature range between 250 and 325 °C; the lowest values of pv were obtained for the two dicationic liquids, suggesting that they are particularly well suited for high temperature applications. The vaporization enthalpy was calculated through the Clausius-Clapeyron equation and was found in the range between ~140 and ~180 kJ/mol depending on the specific IL.

Host Cell Proteases Mediating SARS-CoV-2 Entry: An Overview.

The outbreak of the SARS-CoV-2 virus in late 2019 and the spread of the COVID-19 pandemic have caused severe health and socioeconomic damage worldwide. Despite the significant research effort to develop vaccines, antiviral treatments, and repurposed therapeutics to effectively contain the catastrophe, there are no available effective vaccines or antiviral drugs that can limit the threat of the disease, so the infections continue to expand. To date, the search for effective treatment remains a global challenge. Therefore, it is imperative to develop therapeutic strategies to contain the spread of SARS-CoV-2. Like other coronaviruses, SARS-CoV-2 invades and infects human host cells via the attachment of its spike envelope glycoprotein to the human host cell receptor hACE2. Subsequently, several host cell proteases facilitate viral entry via proteolytic cleavage and activation of the S protein. These host cell proteases include type II transmembrane serine proteases (TTSPs), cysteine cathepsins B and L, furin, trypsin, and Factor Xa, among others. Given the critical role of the host cell proteases in coronavirus pathogenesis, their inhibition by small molecules has successfully targeted SARS-CoV-2 in vitro, suggesting that host cell proteases are attractive therapeutic targets for SARS-CoV-2 infection. In this review, we focus on the biochemical properties of host cell proteases that facilitate the entry of SARS-CoV-2, and we highlight therapeutic small molecule candidates that have been proposed through in silico research.

Ethane-1,1,2-trisphosphonic acid hemihydrate.

Ethane-1,1,2-trisphosphonic acid crystallizes as a hemihydrate, C(2)H(9)O(9)P(3).0.5H(2)O, in which the water O atom lies on an inversion centre in the space group P2(1)/c. The acid component, which contains a short but noncentred O-H...O hydrogen bond, adopts a gauche conformation. The acid components are linked by an extensive series of O-H...O hydrogen bonds to form layers, which are linked into pairs by the water molecules.

In Silico SAR Studies of HIV-1 Inhibitors.

Quantitative Structure Activity Relationships (QSAR or SAR) have helped scientists to establish mathematical relationships between molecular structures and their biological activities. In the present article, SAR studies have been carried out on 89 tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine (TIBO) derivatives using different classifiers, such as support vector machines, artificial neural networks, random forests, and decision trees. The goal is to propose classification models that will be able to classify TIBO compounds into two groups: high and low inhibitors of HIV-1 reverse transcriptase. Each molecular structure was encoded by 10 descriptors. To check the validity of the established models, all of them were subjected to various validation tests: internal validation, Y-randomization, and external validation. The established classification models have been successful. The correct classification rates reached 100% and 90% in the learning and test sets, respectively. Finally, molecular docking analysis was carried out to understand the interactions between reverse transcriptase enzyme and the TIBO compounds studied. Hydrophobic and hydrogen bond interactions led to the identification of active binding sites. The established models could help scientists to predict the inhibition activity of untested compounds or of novel molecules prior to their synthesis. Therefore, they could reduce the trial and error process in the design of human immunodeficiency virus (HIV) inhibitors.

Evaluation of chiral ionic liquids as additives to cyclodextrins for enantiomeric separations by capillary electrophoresis.

A great interest has been drawn these last years towards ionic liquids in analytical chemistry, especially for separation methods. Recent synthesis of chiral ILs opened the way of the evaluation of new potential selectors for enantiomeric separations. This work focused on the evaluation of two chiral ILs (ethyl- and phenylcholine of bis(trifluoromethylsulfonyl)imide) by CE. Particular selectivities are awaited by exploiting unique ion-ion or ion-dipole interactions and by tailoring the nature of the cation and the anion. To evaluate such phenomena, a study was carried out with anti-inflammatory drugs 2-arylpropionic acids as model compounds. The results show that these chiral ILs did not present direct enantioselectivity with regard to these model analytes. The influence of chiral ILs in the electrolytes was then studied in the presence of classical chiral selectors (di- or trimethyl-beta-cyclodextrin). Although no general trend could be established, an increase in separation selectivity and resolution was observed in some cases, suggesting synergistic effects. The complementary determination of apparent inclusion constant values of these IL cations in the used cyclodextrins by affinity CE provided support to the understanding of the phenomena involved.

Programmed Site-Selective Palladium-Catalyzed Arylation of Thieno[3,2-b]thiophene.

Mono-, di-, tri-, and tetraarylated thieno[3,2-b]thiophenes were synthesized by direct site-selective Pd-catalyzed C-H activation reactions with various aryl bromides in the presence of a phosphine-free Pd(OAc)2 /KOAc catalyst system in N,N-dimethylacetamide (DMAc). The arylation of 2-arylthieno[3,2-b]thiophene took place at the C3 position if the 2-aryl substituents possessed electron-withdrawing groups and at the C5 position if they were bulky and possessed electron-donating groups.

An efficient recyclable magnetic material for the selective removal of organic pollutants.

Wastewater cleaning strategies based on the adsorption of materials are being increasingly considered, but the wide variety of organic pollutants at low concentrations still makes their removal a challenge. The hybrid material proposed here consists of a zwitterionic polyethylenimine polymer coating a magnetic core. Polyethylenimine is phosphonated at different percentages by a one-step process and used to coat maghemite nanoparticles. It selectively extracts high amounts of cationic and anionic contaminants over a wide range of pH values, depending on the adjustable number of phosphonate groups introduced on the polymer. After recovering the nanoparticles with a magnet, pollutants are quantitatively released by repeated washing with low amounts of pH-adjusted water. The material can be reused many times without noticeable loss of efficiency and is designed to resist high temperatures, oxidation and harsh conditions.

Regioselective, stereoselective, and conformationally controlled synthesis of (η4-tetraarylcyclobutadiene)(η5-carbomethoxycyclopentadienyl)cobalt metallocenes.

The Friedel-Crafts reaction of (η(4)-tetraphenylcyclobutadiene)(η(5)-carbomethoxycyclopentadienyl)cobalt with acid chlorides/aluminum chloride resulted exclusively in para-phenyl acylation. Both monoacylated (1.1 equiv of RCOCl/AlCl(3)) and tetraacylated products (>4 equiv of RCOCl/AlCl(3)) were synthesized. Reaction of PhCC(o-RC(6)H(4)) (R = Me, i-Pr) with Na(C(5)H(4)CO(2)Me) and CoCl(PPh(3))(3) gave predominantly (η(4)-1,3-diaryl-2,4-diphenylcyclobutadiene)(η(5)-carbomethoxycyclopentadienyl)cobalt metallocenes (1,3-[trans] vs 1,2-[cis] selectivity up to 6:1). Conformational control of Friedel-Crafts reactions on the major isomers gave exclusively para-acylation of the unsubstituted phenyl groups.