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Abstract: This work describes the synthesis of 2-iodo-3,4,5-trimethoxybenzoic acid. The combination of iodine and silver trifluoroacetate (AgTFA) reagents was used successfully for the iodination of 3,4,5-trimetoxybenzoic acid. To improve the efficiency of the synthetic process a significant modification on the experimental design was also performed. The main structural features of the obtained aryl iodide were investigated by a single crystal X-ray diffraction analysis, FTIR, 1H and 13C NMR spectroscopy. [Copyright &y& Elsevier]

In this paper, I address word order variation in root clauses in Middle Low German (MLG). This historical stage, neglected in previous formal research on word order, is remarkable in that it displays well-known properties of modern continental West-Germanic syntax, above all verb-second order in root clauses, but at the same time allows violations against this constraint. By using diagnostic evidence, I show that orders violating the verb-second rule are of two types: (i) clauses in which no verb fronting applies, and (ii) clauses in which the finite verb is moved to the left periphery but not to the second position, allowing more than one XP to precede it. The latter order is referred to as multiple XP-fronting and is the subject of detailed analysis. Given the fact that modern German also allows multiple XP-fronting under certain conditions that are compatible with the verb-second rule, I show that the properties of multiple XP-fronting in MLG are of a different kind. More importantly, fronted XPs in multiple XP-fronting constructions in MLG display robust ordering principles with respect to information structure, which supports an analysis in line with the cartographic approach to the structure of the left periphery put forward by Rizzi (). [ABSTRACT FROM AUTHOR]

The paper reports on a simple method of synthesizing [PEO(PCL)] triarm star-shaped copolymers by a combination of Michael-addition type reaction and ring-opening polymerization. A Michael-addition reaction yielded a PEO end-capped by two hydroxyl groups-a [PEO(OH)] macroinitiator-which was used for sequential building of PCL blocks. The macroinitiator and copolymers were analyzed by FTIR, H NMR spectroscopy and SEC. The self-assembly behavior of the copolymers in aqueous media was studied by UV-Vis spectroscopy. The size and morphology of the obtained micelles were determined by TEM. None of the polymers had cytotoxic effects in vitro. Cellular uptake studies showed the accumulation of neutral red loaded micelles in the perinuclear area of human hepatocellular carcinoma cells revealing a cellular uptake associated with macropinocytosis and caveolae mediated endocytosis. The accumulation had a sustained effect over 3 days pointing at the potential application of the copolymers micelles as a drug delivery system. [ABSTRACT FROM AUTHOR]

Abstract: Addressing the current debate on the mapping between focus marking and focus interpretation, the paper presents evidence suggesting that different types of focus correlate with different types of movement of DP-objects in Old English. The analysis of the contexts in which these movement operations occur reveals that if we assume a double base scenario allowing for optional movement both to the left and to the right of the IP, we obtain orders in which the objects firmly correlate with a particular information-structural property. While movement to the left takes place in those cases in which the referent of the object is in a contrastive relation to another entity in the context, rightward movement clearly relates to novelty in the discourse. [Copyright &y& Elsevier]

Abstract: Declarative clauses in Old High German (OHG) display V1- and V2-orders. In this paper, we show that verb placement in OHG is determined by information-structural (IS-) conditions: the verb serves to separate the aboutness topic from the rest of the clause (the comment). In this system, V1-clauses appear in sentences that lack a topic-comment division. The generalization of the V2 rule in German came about by extending the pattern representing topic comment structures onto sentences representing other discourse relations. In this process, the sentence-initial position was IS-neutralized, supporting an analysis of V2 in the modern language as verb movement to a unique head position with an EPP-feature. We compare this scenario with the system of verb placement in Old English (OE) and argue that English did not develop a generalized V2 rule, since the position of the verb in OE did not serve to separate a special topic from the rest of the clause, but separated all background elements from the focus domain of the clause. Finally, we argue that the V2-pattern in OHG derives from a construction in which a topic and a V1-clause were juxtaposed. Thus, the historic scenario as a whole provides support for the analysis of V2 in German as being derived from an original V1 system. [Copyright &y& Elsevier]

Abstract: This paper describes the synthesis of a novel amphiphilic AB2 triarm star-shaped copolymer with A=non-toxic and biocompatible hydrophilic poly(ethylene oxide) (PEO) and B=biodegradable and hydrophobic poly(ε-caprolactone) (PCL). A series of AB2 triarm star-shaped copolymers with different molecular-weights for the PCL block were successfully synthesized by a three-step procedure. α-Methoxy-ω-epoxy-poly(ethylene oxide) (PEO-epoxide) was first synthesized by the nucleophilic substitution of α-methoxy-ω-hydroxy-poly(ethylene oxide) (MPEO) on epichlorohydrin. In a second step, the α-methoxy-ω,ω′-dihydroxy-poly(ethylene oxide) (PEO(OH)2) macroinitiator was prepared by the selective hydrolysis of the ω-epoxy end-group of the PEO-epoxide chain. Finally, PEO(OH)2 was used as a macroinitiator for the ring-opening polymerization (ROP) of ε-caprolactone (εCL) catalyzed by tin octoaote (Sn(Oct)2). PEO-epoxide, PEO(OH)2 and the AB2 triarm star-shaped copolymers were assessed by 1H NMR spectroscopy, size exclusion chromatography (SEC) and MALDI-TOF. The behavior of the AB2 triarm star-shaped copolymer in aqueous solution was studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). [Copyright &y& Elsevier]

Background and Objective: The goal of this paper is to perform a comparative study of the capabilities of optical coherence tomography (OCT) and fluorescence spectroscopy for detection of neoplastic processes and malignant tumor borders in the uterine cervix and vulva, and to preliminarily analyze the advisability of using these two methods complementarily.Study Design/Materials and Methods:Using the two methods-fluorescence spectroscopy, which is based on the detection of biochemical changes in tissue, and optical coherence tomography that detects morphologic or structural tissue information-borders of neoplasia in the uterine cervix and vulva were determined. A parallel analysis of optical properties of tissue and histologic material taken from the center of tumor and the OCT-detected boundary was performed; the visual and optically detected borders of the pathological zone were compared. A total of 12 women with neoplasia in the uterine cervix and vulva were enrolled in this study.Results: First results of this study show that an optically detected demarcation line of cervical neoplasia is farther from the tumor focus by an average of 2 mm than a colposcopically determined border. It was verified that the OCT-detected borders morphologically coincided with the real histologic borders. The OCT and fluorescence spectroscopy yielded the same results in only some experiments. In several clinical cases, it was difficult to interpret OCT images (combination with scar changes in the uterine cervix) and fluorescence spectroscopy data (combination with inflammatory changes).Conclusions: Experimental data presented here show the capability of OCT imaging and fluorescence spectroscopy to detect borders of neoplastic processes in the uterine cervix and vulva more accurately than conventional colposcopy. The results of this study provide a rationale for using these optical techniques in combination as complementary objective methods of cancer diagnostics. [ABSTRACT FROM AUTHOR]

This study investigated a library of known and novel glycyrrhizic acid (GL) conjugates with amino acids and dipeptide esters, as inhibitors of the DENV NS2B-NS3 protease. We utilized docking algorithms to evaluate the interactions of these GL derivatives with key residues (His51, Asp75, Ser135, and Gly153) within 10 Å of the DENV-2 NS2B-NS3 protease binding pocket (PDB ID: 2FOM). It was found that compounds 11 and 17 exhibited unique binding patterns, forming hydrogen bonds with Asp75, Tyr150, and Gly153. Based on the molecular docking data, conjugates 11 with L-glutamic acid dimethyl ester, 17 with β-alanine ethyl ester, and 19 with aminoethantic acid methyl ester were further demonstrated as potent inhibitors of DENV-2 NS3 protease, with IC50 values below 1 μM, using NS3-mediated cleavage assay. Compound 11 was the most potent, with EC50 values of 0.034 μM for infectivity, 0.042 μM for virus yield, and a selective index over 2000, aligning with its strong NS3 protease inhibition. Compound 17 exhibited better NS3 protease inhibition than compound 19 but showed weaker effects on infectivity and virus yield. While all compounds strongly inhibited viral infectivity post-entry, compound 19 also blocked viral entry. This study provided valuable insights into the interactions between active GL derivatives and DENV-2 NS2B-NS3 protease, offering a comprehensive framework for identifying lead compounds for further drug optimization and design as NS2B-NS3 protease inhibitors against DENV. [ABSTRACT FROM AUTHOR]

Here, we report on the construction of biodegradable poly(ethylene oxide monomethyl ether) (MPEO)-b-poly(ε-caprolactone) (PCL) nanoparticles (NPs) having acid-labile (acyclic ketal group) linkage at the block junction. In the presence of acidic pH, the nanoassemblies were destabilized as a consequence of cleaving this linkage. The amphiphilic MPEO-b-PCL diblock copolymer self-assembled in PBS solution into regular spherical NPs. The structure of self-assemble and disassemble NPs were characterized in detail by dynamic (DLS), static (SLS) light scattering, small-angle X-ray scattering (SAXS), and transmission electron microscopy (TEM). The key of the obtained NPs is using them in a paclitaxel (PTX) delivery system and study their in vitro cytostatic activity in a cancer cell model. The acid-labile ketal linker enabled the disassembly of the NPs in a buffer simulating an acidic environment in endosomal (pH ~5.0 to ~6.0) and lysosomal (pH ~4.0 to ~5.0) cell compartments resulting in the release of paclitaxel (PTX) and formation of neutral degradation products. The in vitro cytotoxicity studies showed that the activity of the drug-loaded NPs was increased compared to the free PTX. The ability of the NPs to release the drug at the endosomal pH with concomitant high cytotoxicity makes them suitable candidates as a drug delivery system for cancer therapy. [ABSTRACT FROM AUTHOR]

A rapid and eco-friendly reversible addition-fragmentation chain transfer (RAFT) polymerization reaction of the N -(2-hydroxypropyl) methacrylamide (HPMA) monomer under microwave irradiation (MWI) was demonstrated. A systematic investigation to determine the optimal conditions for the polymerization, such as the reaction time, solvents, monomer stoichiometry and RAFT agents, was implemented. The polymerization kinetics were obtained using two different chain transfer agents (CTAs), namely, commercial 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid and synthesized 4-cyano-4-(((ethylthio)carbonothioyl)thio)pentanoic acid, in the presence of 4,4′-azobis(4-cyanovaleric acid) as the initiator in various solvents. The controlled living character of the RAFT polymerization under MWI conditions was demonstrated by the linear increase in the number-average molecular weight (M n) with monomer conversion. Moreover, good agreement between the theoretical and experimental M n values was verified with pseudo-first-order kinetic plots, with low dispersities (Đ ≤ 1.04) if a favorable solvent and/or CTA was chosen. In addition, the ability of MWI to facilitate copolymer formation was demonstrated by the preparation of relevant copolymers, such as poly(HPMA- b -bocAPMA), poly(HPMA- b -MABH) and poly(HPMA- b -PDPA). Altogether, these facile synthetic approaches can find applications for the synthesis of PHPMA-based homo- and copolymers that have already been clinically tested and serve as hydrophilic high-potential alternatives to polyethylene oxide. [Display omitted] • Rapid and eco-friendly RAFT polymerization reaction under microwave irradiation (MWI). • Rapid synthesis of biomedical relevant homo and copolymers of poly[ N -(2-hydroxypropyl) methacrylamide] (PHPMA). • Facile synthetic approach for the synthesis of PHPMA-based homo- and copolymers as hydrophilic potential alternatives to PEO. [ABSTRACT FROM AUTHOR]

Probiotics can act as an alternative to antibiotics in animal feeding, but their use is minimal due to their expensive production. Dry grass is rich with bacteria beneficial for animal feeding and can be used as a probiotic. However, data about the quantitative dependence of the grass microbiome on environmental factors and seasons remain insufficient for preparing "grass-meal-based probiotics". Four grass samples were collected in two geographically remote regions of Russia; their microbiome was characterized by metagenomic sequencing of 16S rDNA libraries and microbiological seeding, and biological testing of the grass meal was carried out on 6 groups of birds containing 20 Ross 308 cross broilers each for a period of 42 days. The positive control group (PC) obtained 16–25 mg/mL toltrazuril (coccidiostatic agent) and 0.5 mL/L liquid antibiotic enrostin (100 mg/mL ciprofloxacin and 106 MU/mL colistin sulfate in the commercial preparation) within the drinking water, while the negative control group (NC) obtained no medicines. Four experimental groups were fed the diet supplemented with 1% grass meal over the period of 7–42 days of life; no commercial medicines were used here. A spontaneous infection with Eimeria was registered in the NC control groups, which caused the loss of 7 chickens. No losses were registered in the PC group or the two experimental groups. In two other experimental groups, losses of coccidiosis amounted to 10% and 15%, respectively. All specimens of the grass meal demonstrated a significant effect on the average body weight gain compared to NC. Taken together, these observations support the hypothesis that the grass meal may substitute toltrazuril for protecting the chickens from parasitic invasion and increase average daily weight gain (ADG) as effectively as the antibiotic enrostin. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this research was to compare root exudation of major organic components, effects of PGPR on root exudates and the response of different soybean varieties to inoculation with PGPR to understand variety-dependent relationships between these traits. Methods: Growth and root exudation of soybean varieties Nice-Mecha, Bara and Svapa in the absence and presence of PGPR Pseudomonas oryzihabitans Ep4 was studied using gnotobiotic hydroponic system and UPLC techniques. Rhizobacterial effects on growth, seed yield quality, nodulation by Bradyrhizobium japonicum 634b and uptake of nutrients was investigated under field conditions. Results: Genotypic differences between soybean varieties in root exudation, rhizobacterial effects on exudation and interactions with Ps. oryzihabitans Ep4 were revealed. Variety Bara had greatest root biomass with least root exudation and least Ps. oryzihabitans Ep4 colonisation. In both hydroponic experiments and field trials, the varieties Nice-Mecha and particularly Svapa responded more actively to Ps. oryzihabitans Ep4 than the variety Bara. Several mechanisms related to root exudation rate, exudate composition, bacterial production of siderophores and auxins are proposed to explain variety dependent interactions of plants with PGPR. Conclusions: The variety specific plant response to PGPR is mediated by genotypic differences in root exudation and the ability of PGPR to metabolize and/or transform the exuded organic acids, sugars and amino acids. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is one of the most geographically distributed mosquito-borne flaviviruses, like Japanese encephalitis virus (JEV), and Zika virus (ZIKV). In this study, a library of the known and novel Glycyrrhizic acid (GL) derivatives bearing amino acid residues or their methyl/ethyl esters in the carbohydrate part were synthesized and studied as DENV inhibitors in vitro using the cytopathic effect (CPE), viral infectivity and virus yield assays with DENV1 and DENV-2 in Vero E6 and A549 cells. Among the GL conjugates tested, compound hits GL-D-ValOMe 3, GL-TyrOMe 6, GL-PheOEt 11, and GL-LysOMe 21 were discovered to have better antiviral activity than GL, with IC50 values ranging from <0.1 to 5.98 μM on the in vitro infectivity of DENV1 and DENV2 in Vero E6 and A549 cells. Compound hits 3, 6, 11, and 21 had a concentration-dependent inhibition on the virus yield in Vero E6, in which GL-D-ValOMe 3 and GL-PheOEt 11 were the most active inhibitors of DENV2 yield. Meanwhile, the time-of-addition assay indicated that conjugates GL-D-ValOMe 3 and GL-PheOEt 11 exhibited a substantial decrease in the DENV2 attachment stage. Subsequently, chimeric single-round infectious particles (SRIPs) of DENV2 C-prM-E protein/JEV replicon and DENV2 prM-E/ZIKV replicon were utilized for the DENV envelope I protein-mediated attachment assay. GL conjugates 3 and 11 significantly reduced the attachment of chimeric DENV2 C-prM-E/JEV and DENV2 prM-E/ZIKV SRIPs onto Vero E6 cells in a concentration-dependent manner but did not impede the attachment of wild-type JEV CprME/JEV and ZIKV prM-E/ZIKV SRIPs, indicating the inhibition of Compounds 3 and 11 on DENV2 E-mediated attachment. Molecular docking data revealed that Compounds 3 and 11 have hydrophobic interactions within a hydrophobic pocket among the interfaces of Domains I, II, and the stem region of the DENV2 envelope (E) protein. These results displayed that Compounds 3 and 11 were the lead compounds targeting the DENV E protein. Altogether, our findings provide new insights into the structure–activity relationship of GL derivatives conjugated with amino acid residues and can be the new fundamental basis for the search and development of novel flavivirus inhibitors based on natural compounds. [ABSTRACT FROM AUTHOR]

[MediaObject not available: see fulltext.]The reaction of 1,4-dioxanyl peroxyl radical with 5-amino-6-methyluracil gave the following major products: 5,5,6-trihydroxy-6-methyldihydropyrimidine-2,4(1 H,3 H)-dione, 6-hydroxy-6-methyldihydropyrimidine-2,4,5(3 H)-trione, and 6-hydroxy-5-hydroxyimino-6-methyldihydropyrimidine-2,4(1 H,3 H)-dione. A radical chain reaction mechanism was proposed for the oxidation of 1,4-dioxane in the presence of 5-amino-6-methyluracil. [ABSTRACT FROM AUTHOR]

An exclusively stereoselective reaction of AcOH elimination in the title acetate of cloprostenol was described, which led with high yield under Pd(PPh 3) 4 -NaH-THF catalysis to the corresponding 13E,15Z-derivative. In contrast, under the same conditions, the use of methyl ester of 15-acetate 11-deoxyprostaglandin E1 results in regioisomeric reductive elimination products. [Display omitted] • The reaction of prostaglandin with NaH in the presence of a Pd catalyst was target. • Relationships between configuration and energy of unsaturated alcohols were shown. • The structures were optimized by quantum chemical modeling methods. • Elimination products and reductive elimination products were obtained. • The structure of the obtained compounds was thoroughly determined by NMR. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2 , 6 , 9 , and 15 , with methionine methyl esters, D-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17–152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 μM) and Mpro_Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants. [Display omitted] • GL conjugates with MetOMe, D-TyrOMe, Glu(OH)-Ome, and Met show antiviral ability. • They markedly inhibit wild-type Mpro proteolytic activity with IC50 < 0.85 μM. • They effectively reduce trans-cleavage activity by Mpro_E166V, surpassing Nirmatrelvir. • They exhibit stronger interactions with Valine166 in Mpro_E166V than Nirmatrelvir. • They greatly decrease Mpro_E166V SARS-CoV-2 infectivity compared to Nirmatrelvir. [ABSTRACT FROM AUTHOR]

Bioactive moieties designed to bind to cell membrane receptors benefit from coupling with polymeric carriers that have enhanced affinity to the cell membrane. When bound to the cell surface, such carriers create a "2D solution" of a ligand with a significantly increased concentration near a membrane-bound receptor compared to a freely water-soluble ligand. Bifunctional polymeric carriers based on amphiphilic triblock copolymers were synthesized from 2-pent-4-ynyl oxazoline, 2-nonyl oxazoline and 2-ethyl oxazoline. Their self-assembly and interactions with plasma proteins and HEK 293 cells were studied in detail. The affinity of these triblock copolymers to HEK 293 cell membranes and organ tissues was tunable by the overall hydrophobicity of the polymer molecule, which is determined by the length of the hydrophobic and hydrophilic blocks. The circulation time and biodistribution of three representative triblock copolymers were monitored after intravenous administration to C57BL/6 albino mice. A prolonged circulation time was observed for polymers with longer hydrophobic blocks, despite their molecular weight being below the renal threshold. [Display omitted] • Amphiphilic polyoxazolines are versatile platforms for carrying the bioactive moieties. • Hydrophobicity of polyoxazolines is adjusted by the length of individual blocks. • Affinity of polyoxazolines to proteins and cells is determined by their hydrophobicity. [ABSTRACT FROM AUTHOR]

H NMR spectroscopy was used for the first time to investigate temperature behaviour of aqueous solutions of nanoparticles (NPs) prepared from linear and Y-shape terpolymers containing blocks of poly(ethylene oxide) (PEO), poly(2-ethyl-2-oxazoline) (PEtOx) and one linear or two star poly(ε-caprolactone) (PCL) blocks with different length. Structural changes were characterized separately for all blocks in a temperature range 295-360 K, and a broad transition was observed at temperatures above ~320 K. The temperature behaviour of NPs solutions depends on polymer concentration and especially on terpolymer architecture. At the same time, NMR measurements revealed important role of PCL blocks in this behaviour. The spin-spin relaxation times T of water (HDO) give information on the behaviour of water and on polymer-water interactions within the aforementioned temperature range. In NPs solutions of the linear copolymer, two types of water were detected at higher temperatures: 'free' and 'bound' water molecules with long and very short T values, respectively. For NPs solution of non-linear terpolymer, two types of water were observed only for the highest used (1.5 wt%) polymer concentration. [ABSTRACT FROM AUTHOR]

Brachytherapy represents effective local therapy of unresectable solid tumors with very few side effects. Radiolabeled thermoresponsive polymers offer almost noninvasive approach to brachytherapy applications. A radioiodinated, water-soluble, thermosensitive poly( N -vinylcaprolactam) (PVCL) polymer was prepared using two approaches. The direct copolymerization with N -methacryloyl- l -tyrosinamide, as well as end-capping of carboxy-terminated PVCL homopolymer with tyramine, were used. In both cases the product was successfully radiolabeled with 125 I. The obtained polymers demonstrate cloud-point temperature ( T C ) values in the range of 33–35 °C in all the studied solvent systems (water, PBS (pH 7.4) and physiological saline solution). Above the cloud point temperature, the molecularly dissolved polymer is macroprecipitated from the solution. The T C values close to the human body temperature of this biocompatible poly( N -vinylcaprolactam) polymer makes it a promising material intended for local therapy of solid tumors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Glycyrrhetinic acid (GA) derivatives (amides, semi- and thiosemicarbazones, and 1,2,3-thiadiazoles) were synthesized and tested as Zika virus inhibitors in vitro. • Four active compounds were found among GA derivatives tested with IC 50 < 1 μM against ZIKV replication. The lead compound was amide 13 containing 2-aminopyridine residue (IC 50 0.13 μM, TI ˃ 384). • Time-of-addition assays indicated the second lead compound 19 (1,2,3-thiadiazole 30-butyl GA) effectively inhibiting viral entry and post-entry stages. • The molecular docking analysis demonstrated that lead compounds 13 and 19 forms a hydrogen-bond interaction with the catalytic triad (His51 - Asp75-Ser135) of ZIKV NS2B-NS3 protease. Zika virus (ZIKV) is an arbovirus of the Flaviviridae family (Flavivirus genus), causing serious neurological complications, such as Guillain-Barre Syndrome (GBS) in adults and fetal microcephaly. Licensed vaccines or specific antiviral agents against ZIKV do not currently exist. Therefore, the search and development of anti-ZIKV agents are particularly relevant and necessary. Glycyrrhetinic (3 β -hydroxy-11-oxo-18 β H-Olean-12-en-30-oic acid) (GA) 1 is one of the well-known pentacyclic triterpenoids isolated from licorice root (Glycyrrhiza glabra L., Gl. uralensis Fisher) (Leguminosae) possessing many biological features, including antiviral activity. This paper is devoted to the synthesis and studies of a number of nitrogen and sulfur-containing GA derivatives as ZIKV inhibitors. Sixteen GA and related triterpenoids (3 β -hydroxy-18 β H-Olean-12-en-30-oic acid and 3 β -hydroxy-11-oxo-18 β H-Olean-12(13),18(19)-dien-30-oic acid) derivatives were synthesized (amides, semi- and thiosemicarbazones, and 1,2,3-thiadiazoles) and antiviral activity against ZIKV was studied in vitro , including the inhibitory assays on cytopathic effect (CPE), viral protein synthesis, and replication stages. Four active compounds were found among GA derivatives tested, 13 (3-O-acetyl-30-aminopyridine GA), 16 (3-semicarbazone-30-butyl GA), 18 (1,2,3-thiadiazole-30-methyl GA), and 19 (1,2,3-thiadiazole-30-butyl GA) with IC 50 < 1 μM against ZIKV replication. These compounds had a stronger inhibitory activity on ZIKV-induced CPE and viral protein translation in infected cells as compared to derivatives of 11-desoxo-GA. The most active compound was amide 13 (IC 50 0.13 μM, TI ˃ 384). Time-of-addition assays indicated that 1,2,3-thiadiazole ring is important for inhibiting viral entry stage (compounds 18 and 19), while the 30-butyl ester group influenced on post-entry stage (compound 19). The molecular docking analysis demonstrated that lead compounds 13 and 19 forms a hydrogen-bond interaction with the catalytic triad (His51 - Asp75-Ser135) of ZIKV NS2B-NS3 protease. Therefore, the active GA derivatives are promising for developing new antiviral agents against ZIKV infection. [ABSTRACT FROM AUTHOR]

• It is the first report about the ant-ZIKV activity of Glycyrrhizic acid (GL) and its derivatives. • The amino acid residues in the carbohydrate part maintain anti-ZIKV activity of GL derivatives. • GL conjugates with Asp(OMe)-OMe 13 and TyrOMe 14 were identified as potent ZIKV inhibitors. • Molecular docking discovered the interaction of compounds 13 and 14 with the active site of NS5 MTase. Zika virus (ZIKV) is a new pathogenic flavivirus transmitted by mosquitoes Aedes spp. ZIKV infection is accompanied by serious neurological complications and is especially dangerous for pregnant women, in which it can lead to congenital malformations of the fetus and microcephaly in neonates. Currently, there are no licensed vaccines or specific post-infectious therapies for ZIKV infection. This report is devoted to the study of glycyrrhizic acid (GL) derivatives as ZIKV inhibitors. The inhibitory assays on the cytopathic effect (CPE) and viral infectivity of ZIKV in three different human cell lines revealed that the conjugation of GL with amino acids and their esters (methyl, ethyl) is influenced by the antiviral activity of the compounds. GL conjugates with Glu(OMe)-OMe 11 , Glu(OH)-OMe 12 , Asp(OMe)-OMe 13 , TyrOMe 14 , LeuOEt 15 , and PheOEt 16 with free COOH groups in the triterpene moiety were active against ZIKV. The most active compounds 13 and 14 have IC50 values of 0.23 μM and 0.09 μM against low doses (MOI = 0.05) of ZIKV strain PRVABC59, 1.20 μM and 0.74 μM against high doses (MOI = 10) of ZIKV strain Natal RGN single-round infectious particles, respectively. The lead compound was 14 with a high selectivity index (SI < 500). Compound 13 showed a higher inhibitory effect on the early stage (entry) of ZIKV replication than compound 14 , and was less potent than compound 14 at the post-entry stage, consistent with the docking models. Compounds 13 and 14 also had a strong interaction with the active site pocket of NS5 MTase. Compounds 13 and 14 are recommended for expanded antiviral studies against ZIKV infection. [ABSTRACT FROM AUTHOR]

• It is the first report to display structure-anti-DENV activity relationships of Glycyrrhizic acid (GL) derivatives. • GL conjugates with isoleucine 13 and 11-aminoundecanoic acid 17 have been identified as potent DENV2 inhibitors. • GL derivatives 13 and 17 showed lower IC50 values (1.2–1.3 μM) against DENV2 infectivity in Vero E6 cells than GL (IC50 8.1 μM). Dengue virus (DENV) is one of the most geographically distributed pathogenic flaviviruses transmitted by mosquitoes Aedes sps. In this study, the structure-antiviral activity relationships of Glycyrrhizic acid (GL) derivatives was evaluated by the inhibitory assays on the cytopathic effect (CPE) and viral infectivity of DENV type 2 (DENV2) in Vero E6 cells. GL (96% purity) had a low cytotoxicity to Vero E6 cells, inhibited DENV2-induced CPE, and reduced the DENV-2 infectivity with the IC50 of 8.1 μM. Conjugation of GL with amino acids or their methyl esters and the introduction of aromatic acylhydrazide residues into the carbohydrate part strongly influenced on the antiviral activity. Among compounds tested GL conjugates with isoleucine 13 and 11-aminoundecanoic acid 17 were found as potent anti-DENV2 inhibitors (IC50 1.2–1.3 μM). Therefore, modification of GL is a perspective way in the search of new antivirals against DENV2 infection. [ABSTRACT FROM AUTHOR]