Agaricus bisporus Crude Extract: Characterization and Analytical Application

In the present work crude Agaricus bisporus extract (ABE) has been prepared and characterized by its tyrosinase activity, protein composition and substrate specificity. The presence of mushroom tyrosinase (PPO3) in ABE has been confirmed using two-dimensional electrophoresis, followed by MALDI TOF/TOF MS-based analysis. GH27 alpha-glucosidases, GH47 alpha-mannosidases, GH20 hexosaminidases, and alkaline phosphatases have been also detected in ABE. ABE substrate specificity has been studied using 19 phenolic compounds: polyphenols (catechol, gallic, caffeic, chlorogenic, and ferulic acids, quercetin, rutin, dihydroquercetin, l-dihydroxyphenylalanine, resorcinol, propyl gallate) and monophenols (l-tyrosine, phenol, p-nitrophenol, o-nitrophenol, guaiacol, o-cresol, m-cresol, p-cresol). The comparison of ABE substrate specificity and affinity to the corresponding parameters of purified A. bisporus tyrosinase has revealed no major differences. The conditions for spectrophotometric determination have been chosen and the analytical procedures for determination of 1.4 × 10⁻⁴–1.0 × 10⁻³ M l-tyrosine, 3.1 × 10⁻⁶–1.0 × 10⁻⁴ M phenol, 5.4 × 10⁻⁵–1.0 × 10⁻³ M catechol, 8.5 × 10⁻⁵–1.0 × 10⁻³ M caffeic acid, 1.5 × 10⁻⁴–7.5 × 10⁻⁴ M chlorogenic acid, 6.8 × 10⁻⁵–1.0 × 10⁻³ M l-DOPA have been proposed. The procedures have been applied for the determination of l-tyrosine in food supplements, l-DOPA in synthetic serum, and phenol in waste water from the food manufacturing plant. Thus, we have demonstrated the possibility of using ABE as a substitute for tyrosinase in such analytical applications, as food supplements, medical and environmental analysis.     

Enzyme repurposing of a hydrolase as an emergent peroxidase upon metal binding

As an alternative to Darwinian evolution relying on catalytic promiscuity, a protein may acquire auxiliary function upon metal binding, thus providing it with a novel catalytic machinery. Here we show that addition of cupric ions to a 6-phosphogluconolactonase 6-PGLac bearing a putative metal binding site leads to the emergence of peroxidase activity (k_cat 7.8 × 10^–2 s^–1, K_M 1.1 × 10^–5 M). Both X-ray crystallographic and EPR data of the copper-loaded enzyme Cu·6-PGLac reveal a bis-histidine coordination site, located within a shallow binding pocket capable of accommodating the o-dianisidine substrate.     

Effects of BPZ and BPC on Oxidative Stress of Zebrafish under Different pH Conditions

To further understand the toxic effects of bisphenol Z (BPZ) and bisphenol C (BPC) on aquatic organisms, zebrafish (Danio rerio) were exposed to 0.02 mg/L BPZ and BPC mixed solution in the laboratory for 28 days. The impacts of BPZ and BPC on the activity of the antioxidant enzymes, expression of antioxidant genes, and estrogen receptor genes in zebrafish under different pH conditions were studied. The changes of glutathione peroxidase (GSH-Px), reduced glutathione (GSH), total superoxide dismutase (T-SOD), catalase (POD), and malondialdehyde (MDA) in the zebrafish were detected by spectrophotometry. The mRNA relative expression levels of CAT, GSH, SOD, ERa, and ERb1 in the experimental group were determined by fluorescence quantitative PCR. The results showed that SOD activity and MDA content were inhibited under different pH conditions, and the activities of GSH, GSH-Px, and POD were induced. The activities of POD and GSH induced in the neutral environment were stronger than those in an acidic and alkaline environment. The mRNA relative expression levels of SOD and GSH were consistent with the activities of SOD and GSH. The mRNA relative expression levels of CAT were induced more strongly in the neutral environment than in acidic and alkaline conditions, the mRNA relative expression levels of ERa were induced most weakly in a neutral environment, and the mRNA relative expression levels of ERb1 were inhibited the most in a neutral environment.     

Electroanalysis of Bisphenols A,F, and Z Using Graphene Based Stochastic Microsensors

Two stochastic microsensors based on immobilization of the complex between protoporphyrin IX and cobalt on nanographene paste and on the reduced graphene oxide paste were proposed for the simultaneous identification and quantification of bisphenols A (BPA), F (BPF) and Z (BPZ) from water samples. The signatures obtained for the BPA, BPF, and BFZ when both stochastic microsensors were used shown that the microsensors can be used for the discrimination between the three bisphenols in water samples. Very low limits of determination were obtained for the three bisphenols: 1fmol/L for BPA and BPF when the microsensor based on the immobilization of the complex between protoporphyrin IX and cobalt on nanographene paste was used, and 10fmol/L for BPZ when the microsensor based on the immobilization of the complex between protoporphyrin IX and cobalt on reduced graphene oxide paste was used. The linear concentration ranges covered by the proposed stochastic microsensors were: between 10^?15 and 10^?5 mol/L for BPA, between 10^?15 and 10^?7 mol/L for BPF, and between 10^?13 and 10^?10 mol/L for BPZ. The recoveries of the bisphenols in water samples were higher than 99.50 %, with RSD values lower than 1.00 %.     

A High Separation Factor for 165Er from Ho for Targeted Radionuclide Therapy

Background: Radionuclides emitting Auger electrons (AEs) with low (0.02–50 keV) energy, short (0.0007–40 µm) range, and high (1–10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide ¹⁷⁷Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce ¹⁶⁵Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Methods: Biomedical cyclotrons proton-irradiated spot-welded Ho_(m) targets to produce ¹⁶⁵Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200–400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20–50 µm, 1.3 mL) and bDGA (50–100 µm, 0.2 mL) extraction chromatography. The purified ¹⁶⁵Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [¹⁶⁵Er]PSMA-617. Results: Irradiation of 80–180 mg ^natHo targets with 40 µA of 11–12.5 MeV protons produced ¹⁶⁵Er at 20–30 MBq·µA⁻¹·h⁻¹. The 4.9 ± 0.7 h radiochemical isolation yielded ¹⁶⁵Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/¹⁶⁵Er separation factor of (2.8 ± 1.1) · 10⁵. Radiolabeling experiments synthesized [¹⁶⁵Er]PSMA-617 at DC molar activities of 37–130 GBq·µmol⁻¹. Conclusions: A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale ¹⁶⁵Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [¹⁶⁵Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer.     

Structural,Optical and Electrical Properties of Cu0.6CoxZn0.4−xFe2O4 (x = 0.0, 0.1, 0.2, 0.3, 0.4) Soft Ferrites

A series of cobalt-inserted copper zinc ferrites, Cu_0.6Co_xZn_0.4−xFe₂O₄ (x = 0.0, 0.1, 0.2, 0.3, 0.4) having cubic spinel structure were prepared by the coprecipitation method. Various characterization techniques, including XRD, FTIR, UV-vis and I–V were used to investigate structural optical and electrical properties, respectively. The lattice constant was observed to be decreased as smaller ionic radii Co²⁺ (0.74 Å) replaced the higher ionic radii Zn²⁺ (0.82 Å). The presence of tetrahedral and octahedral bands was confirmed by FTIR spectra. Optical bandgap energy was determined in the range of 4.44–2.05 eV for x = 0.0 to 0.4 nanoferrites, respectively. DC electrical resistivity was measured and showed an increasing trend (5.42 × 10⁸ to 6.48 × 10⁸ Ω·cm) with the addition of cobalt contents as cobalt is more conductive than zinc. The range of DC electrical resistivity (10⁸ ohm-cm) makes these nanomaterials potential candidates for telecommunication devices.     

Inhibitory Effects of Erythrosine/Curcumin Derivatives/Nano-Titanium Dioxide-Mediated Photodynamic Therapy on Candida albicans

This study focuses on the role of photosensitizers in photodynamic therapy. The photosensitizers were prepared in combinations of 110/220 µM erythrosine and/or 10/20 µM demethoxy/bisdemethoxy curcumin with/without 10% (w/w) nano-titanium dioxide. Irradiation was performed with a dental blue light in the 395–480 nm wavelength range, with a power density of 3200 mW/cm² and yield of 72 J/cm². The production of ROS and hydroxyl radical was investigated using an electron paramagnetic resonance spectrometer for each individual photosensitizer or in photosensitizer combinations. Subsequently, a PrestoBlue^® toxicity test of the gingival fibroblast cells was performed at 6 and 24 h on the eight highest ROS-generating photosensitizers containing curcumin derivatives and erythrosine 220 µM. Finally, the antifungal ability of 22 test photosensitizers, Candida albicans (ATCC 10231), were cultured in biofilm form at 37 °C for 48 h, then the colonies were counted in colony-forming units (CFU/mL) via the drop plate technique, and then the log reduction was calculated. The results showed that at 48 h the test photosensitizers could simultaneously produce both ROS types. All test photosensitizers demonstrated no toxicity on the fibroblast cells. In total, 18 test photosensitizers were able to inhibit Candida albicans similarly to nystatin. Conclusively, 20 µM bisdemethoxy curcumin + 220 µM erythrosine + 10% (w/w) nano-titanium dioxide exerted the highest inhibitory effect on Candida albicans.     

Development and Validation of a Novel HPLC Method to Analyse Metabolic Reaction Products Catalysed by the CYP3A2 Isoform: In Vitro Inhibition of CYP3A2 Enzyme Activity by Aspirin (Drugs Often Used Together in COVID-19 Treatment)

Aspirin (also known as acetylsalicylic acid) is a drug intended to treat fever, pain, or inflammation. Treatment of moderate to severe cases of COVID-19 using aspirin along with dexamethasone has gained major attention globally in recent times. Thus, the purpose of this study was to use High-Performance Liquid Chromatography (HPLC) to evaluate the in vitro inhibition of CYP3A2 enzyme activity using aspirin in rat liver microsomes (RLMs). In this study, an efficient and sensitive HPLC method was developed using a reversed phase C18 column (X Bridge 4.6 mm × 150 mm, 3.5 µm) at 243 nm using acetonitrile and water (70:30 v/v). The linearity (r² > 0.999), precision (<15%), accuracy and recovery (80–120%), limit of detection (5.60 µM and 0.06 µM), limit of quantification (16.98 µM and 0.19 µM), and stability of the newly developed method were validated for dexamethasone and 6β-hydroxydexamethasone, respectively, following International Conference on Harmonization (ICH) guidelines. This method was applied in vitro to measure CYP3A2 activity. The results showed that aspirin competitively inhibits 6β-hydroxylation (CYP3A2 activity) with an inhibition constant (Ki) = 95.46 µM and the concentration of the inhibitor causing 50% inhibition of original enzyme activity (IC₅₀) = 190.92 µM. This indicated that there is a minimal risk of toxicity when dexamethasone and aspirin are co-administrated and a very low risk of toxicity and drug interaction with drugs that are a substrate for CYP3A2 in healthcare settings.     

Complex Activity and Sensor Potential toward Metal Ions in Environmental Water Samples of N-Phthalimide Azo-Azomethine Dyes

Herein, the spectral and electrochemical characterizations of three different substituted N-phthalimide azo-azomethine (NAA) dyes (L) containing an o-hydroxy group and their NAA-M(II) chelates [M(II): Cu, Ni, Co, Pb] were reported by using UV–Vis and fluorescence spectroscopy and potentiometric and voltamperometric techniques. The pK value of the dyes as well as the stoichiometry and stability of the NAA-metal chelates were studied, and the stoichiometry was found to be mostly 1:2 (ML₂) with high complex stability constant values. The sensor activity of N-phthalimide azo-azomethine derivatives toward pH and metal ions has been also investigated and tested for indicator application in acid–base analysis and detection of Cu(II) ions in real samples of surface river water using voltamperometric detection. The results showed that one of the ligands possesses the highest electrochemical response upon binding to copper ions and could be successfully used in the analysis of copper in water at a concentration range of the analyte from 3.7 × 10⁻⁷ to 5.0 × 10⁻⁶ mol L⁻¹, with analytical characteristics of the method being Sr = 1.5%, LOD = 3.58 µg L⁻¹ and LOQ =11.9 µg L⁻¹     

Analytical Performance of Clay Paste Electrode and Graphene Paste Electrode-Comparative Study

The analytical performance of the clay paste electrode and graphene paste electrode was compared using square wave voltammetry (SWV) and cyclic voltammetry (CV). The comparison was made on the basis of a paracetamol (PA) determination on both working electrodes. The influence of pH and SWV parameters was investigated. The linear concentration ranges were found to be 6.0 × 10⁻⁷–3.0 × 10⁻⁵ and 2.0 × 10⁻⁶–8.0 × 10⁻⁵ mol L⁻¹ for clay paste electrode (ClPE) and graphene paste electrode (GrPE), respectively. The detection and quantification limits were calculated as 1.4 × 10⁻⁷ and 4.7 ×10⁻⁷ mol L⁻¹ for ClPE and 3.7 × 10⁻⁷ and 1.2 × 10⁻⁶ mol L⁻¹ for GrPE, respectively. Developed methods were successfully applied to pharmaceutical formulations analyses. Scanning electron microscopy and energy-dispersive X-ray spectroscopy were used to characterize ClPE and GrPE surfaces. Clay composition was examined with wavelength dispersive X-ray (WDXRF).     

Discovery of New Coumarin-Based Lead with Potential Anticancer,CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D QSAR,Molecular Dynamics,In Vitro Cytotoxicity,Radioiodination, and Biodistribution Studies

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r² = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ΔG of –15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an IC₅₀ of 0.0136 µM, 0.015 µM, and 0.054 µM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC₅₀ of 0.036 µM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. ¹³¹I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i. ¹³¹I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.     

Crystallography,Molecular Modeling,and COX-2 Inhibition Studies on Indolizine Derivatives

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC₅₀ of 5.84 µM, as compared to indomethacin (IC₅₀ = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 2₁/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)ų. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.     

Design,Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by ¹H- and ¹³C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC₅₀ value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.     

Antifungal Activity of Chemical Constituents from Piper pesaresanum C. DC. and Derivatives against Phytopathogen Fungi of Cocoa

In this study, the antifungal potential of chemical constituents from Piper pesaresanum and some synthesized derivatives was determined against three phytopathogenic fungi associated with the cocoa crop. The methodology included the phytochemical study on the aerial part of P. pesaresanum, the synthesis of some derivatives and the evaluation of the antifungal activity against the fungi Moniliophthora roreri, Fusarium solani and Phytophthora sp. The chemical study allowed the isolation of three benzoic acid derivatives (1–3), one dihydrochalcone (4) and a mixture of sterols (5–7). Seven derivatives (8–14) were synthesized from the main constituents, of which compounds 9, 10, 12 and 14 are reported for the first time. Benzoic acid derivatives showed strong antifungal activity against M. roreri, of which 11 (3.0 ± 0.8 µM) was the most active compound with an IC₅₀ lower compared with positive control Mancozeb^® (4.9 ± 0.4 µM). Dihydrochalcones and acid derivatives were active against F. solani and Phytophthora sp., of which 3 (32.5 ± 3.3 µM) and 4 (26.7 ± 5.3 µM) were the most active compounds, respectively. The preliminary structure–activity relationship allowed us to establish that prenylated chains and the carboxyl group are important in the antifungal activity of benzoic acid derivatives. Likewise, a positive influence of the carbonyl group on the antifungal activity for dihydrochalcones was deduced.     

Origins of Giant Dielectric Properties with Low Loss Tangent in Rutile (Mg1/3Ta2/3)0.01Ti0.99O2 Ceramic

The Mg²⁺/Ta⁵⁺ codoped rutile TiO₂ ceramic with a nominal composition (Mg_1/3Ta_2/3)_0.01Ti_0.99O₂ was synthesized using a conventional solid-state reaction method and sintered at 1400 °C for 2 h. The pure phase of the rutile TiO₂ structure with a highly dense microstructure was obtained. A high dielectric permittivity (2.9 × 10⁴ at 10³ Hz) with a low loss tangent (<0.025) was achieved in the as-sintered ceramic. After removing the outer surface, the dielectric permittivity of the polished ceramic increased from 2.9 × 10⁴ to 6.0 × 10⁴, while the loss tangent also increased (~0.11). The dielectric permittivity and loss tangent could be recovered to the initial value of the as-sintered ceramic by annealing the polished ceramic in air. Notably, in the temperature range of −60–200 °C, the dielectric permittivity (10³ Hz) of the annealed ceramic was slightly dependent (<±4.4%), while the loss tangent was very low (0.015–0.036). The giant dielectric properties were likely contributed by the insulating grain boundaries and insulative surface layer effects.     

Spectroscopic Studies of Quinobenzothiazine Derivative in Terms of the In Vitro Interaction with Selected Human Plasma Proteins. Part 1

Plasma proteins play a fundamental role in living organisms. They participate in the transport of endogenous and exogenous substances, especially drugs. 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts, have been synthesized as potential anticancer substances used for cancer treatment. Most anticancer substances generate a toxic effect on the human body. In order to check the toxicity and therapeutic dosage of these chemicals, the study of ligand binding to plasma proteins is very relevant. The present work presents the first comparative analysis of the binding of one of the 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium derivatives (Salt1) with human serum albumin (HSA), α-1-acid glycoprotein (AGP) and human gamma globulin (HGG), assessed using fluorescence, UV-Vis and CD spectroscopy. In order to mimic in vivo ligand–protein binding, control normal serum (CNS) was used. Based on the obtained data, the Salt1 binding sites in the tertiary structure of all plasma proteins and control normal serum were identified. Both the association constants (K_a) and the number of binding site classes (n) were calculated using the Klotz method. The strongest complex formed was Salt1–AGP_complex (K_a = 7.35·10⁴ and 7.86·10⁴ mol·L⁻¹ at excitation wavelengths λ_ex of 275 and 295 nm, respectively). Lower values were obtained for Salt1–HSA_complex (K_a = 2.45·10⁴ and 2.71·10⁴ mol·L⁻¹) and Salt1–HGG_complex (K_a = 1.41·10⁴ and 1.33·10⁴ mol·L⁻¹) at excitation wavelengths λ_ex of 275 and 295 nm, respectively, which is a positive phenomenon and contributes to the prolonged action of the drug. Salt1 probably binds to the HSA molecule in Sudlow sites I and II; for the remaining plasma proteins studied, only one binding site was observed. Moreover, using circular dichroism (CD), fluorescence and UV-Vis spectroscopy, no effect on the secondary and tertiary structures of proteins in the absence or presence of Salt1 has been demonstrated. Despite the fact that the conducted studies are basic, from the scientific point of view they are novel and encourage further in vitro and in vivo investigations. As a next part of the study (Part 2), the second new synthetized quinobenzothiazine derivative (Salt2) will be analyzed and published.     

Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys¹¹, Lys¹²,Lys¹³-(pBthTX-I)₂K ((pBthTX-I)₂K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)₂K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC₅₀ = 28–65 µM) and mostly low cytotoxic effect (CC₅₀ > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (M^pro) and Papain-Like protease (PL^pro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL^pro inhibition potencies (IC₅₀s = 1.0–3.5 µM) and binding affinities (K_d = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against M^pro (IC₅₀ > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL^pro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.     

Fe(iii) phytate metallogel as a prototype anhydrous,intermediate temperature proton conductor

A proton conducting metallogel [FNPA; ferric nitrate (FN)–phytic acid (PA)] is synthesized by immobilizing a protogenic ligand (phytic acid) using iron(iii) nitrate in DMF. The xerogel shows high proton conductivity of 2.4 × 10^–2 S cm^–1 at 120 °C, the best value known among all metal organic materials (MOMs). Marking the first such attempt in MOMs, an electrode made using the xerogel showed a power density of 0.94 mW cm^–2 at 0.6 V under dry fuel cell conditions.     

Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreen^TM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC₅₀) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.     

Bile-Acid-Appended Triazolyl Aryl Ketones: Design,Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as ¹H and ¹³C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC₅₀ values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC₅₀ values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC₅₀ = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC₅₀ = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.