Design,Synthesis and Bioactivity Evaluation of Coumarin–BMT Hybrids as New Acetylcholinesterase Inhibitors

Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin–BMT hybrids by introducing coumarin to BMT. In this work, 21 novel hybrids of BMT and coumarin were synthesized and evaluated for their inhibitory activity on AChE. All obtained compounds present preferable inhibition. Compound 8b was the most active compound, with the value of K_i as 49.2 nM, which was higher than Galantamine (GAL) and lower than THA. The result of molecular docking showed that the highest binding free energy was −40.43 kcal/mol for compound 8b, which was an identical trend with the calculated K_i.     

ZnO Nanoparticles of Rubia cordifolia Extract Formulation Developed and Optimized with QbD Application,Considering Ex Vivo Skin Permeation,Antimicrobial and Antioxidant Properties

The objective of the current research is to develop ZnO-Manjistha extract (ZnO-MJE) nanoparticles (NPs) and to investigate their transdermal delivery as well as antimicrobial and antioxidant activity. The optimized formulation was further evaluated based on different parameters. The ZnO-MJE-NPs were prepared by mixing 10 mM ZnSO₄·7H₂O and 0.8% w/v NaOH in distilled water. To the above, a solution of 10 mL MJE (10 mg) in 50 mL of zinc sulfate was added. Box–Behnken design (Design-Expert software 12.0.1.0) was used for the optimization of ZnO-MJE-NP formulations. The ZnO-MJE-NPs were evaluated for their physicochemical characterization, in vitro release activity, ex vivo permeation across rat skin, antimicrobial activity using sterilized agar media, and antioxidant activity by the DPPH free radical method. The optimized ZnO-MJE-NP formulation (F13) showed a particle size of 257.1 ± 0.76 nm, PDI value of 0.289 ± 0.003, and entrapment efficiency of 79 ± 0.33%. Drug release kinetic models showed that the formulation followed the Korsmeyer–Peppas model with a drug release of 34.50 ± 2.56 at pH 7.4 in 24 h. In ex vivo studies ZnO-MJE-NPs-opt permeation was 63.26%. The antibacterial activity was found to be enhanced in ZnO-MJE-NPs-opt and antioxidant activity was found to be highest (93.14 ± 4.05%) at 100 µg/mL concentrations. The ZnO-MJE-NPs-opt formulation showed prolonged release of the MJE and intensified permeation. Moreover, the formulation was found to show significantly (p < 0.05) better antimicrobial and antioxidant activity as compared to conventional suspension formulations.     

Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

MAO-B inhibitors are frequently used in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Due to the limited number of compounds available in this field, there is a need to develop new compounds. In the recent works, it was shown that various thiosemicarbazone derivatives show hMAO inhibitory activity in the range of micromolar concentration. It is thought that benzofuran and benzothiophene structures may mimic structures such as indane and indanone, which are frequently found in the structures of such inhibitors. Based on this view, new benzofuran/benzothiophene and thiosemicarbazone hybrid compounds were synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The compounds including methoxyethyl substituent (2b and 2h) were found to be the most effective agents in the series against MAO-B enzyme with the IC₅₀ value of 0.042 ± 0.002 µM and 0.056 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition of compounds 2b and 2h was investigated by Lineweaver–Burk graphics. Compounds 2b and 2h were reversible and non-competitive inhibitors with similar inhibition features as the substrates. The K_i values of compounds 2b and 2h were calculated as 0.035 µM and 0.046 µM, respectively, with the help of secondary plots. The docking study of compound 2b and 2h revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound.     

N,N-Diethyl-3-toluamide Formulation Based on Ethanol Containing 0.1% 2-Hydroxypropyl-β-cyclodextrin Attenuates the Drug’s Skin Penetration and Prolongs the Repellent Effect without Stickiness

N,N-diethyl-3-toluamide (DEET) is one of the most widely used insect repellents in the world. It was reported that a solution containing 6–30% cyclodextrin (CD) as a solvent instead of ethanol (EtOH) provided an enhancement of the repellent action time duration of the DEET formulation, although the high-dose CD caused stickiness. In order to overcome this shortcoming, we attempted to prepare a 10% DEET formulation using EtOH containing low-dose CDs (β-CD, 2-hydroxypropyl-β-CD (HPβCD), methyl-β-CD, and sulfobutylether-β-CD) as solvents (DEET/EtOH/CD formulations). We determined the CD concentration to be 0.1% in the DEET/EtOH/CD formulations, since the stickiness of 0.1% CDs was not felt (approximately 8 × 10⁻³ N). The DEET residue on the skin superficial layers was prolonged, and the drug penetration into the skin tissue was decreased by the addition of 0.1% CD. In particular, the retention time and attenuated penetration of DEET on the rat skin treated with the DEET/EtOH/HPβCD formulation was significantly higher in comparison with that of the DEET/EtOH formulation without CD. Moreover, the repellent effect of DEET was more sustained by the addition of 0.1% HPβCD in the study using Aedes albopictus. In conclusion, we found that the DEET/EtOH/HPβCD formulations reduced the skin penetration of DEET and prolonged the repellent action without stickiness.     

Improvement in Solubility–Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-β-cyclodextrin

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-β-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-β-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (K_c < 500 M⁻¹). PSO and 5-MOP permeability rate decreased after adding HP-β-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-β-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-β-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.     

Solubility,Permeability, Anti-Inflammatory Action and In Vivo Pharmacokinetic Properties of Several Mechanochemically Obtained Pharmaceutical Solid Dispersions of Nimesulide

Nimesulide (NIM, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (<0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (Na₂GA), hydroxypropyl-β-cyclodextrin (HP-β-CD) and MgCO₃. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by ¹H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, Na₂GA, and HP-β-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered per os to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with Na₂GA and HP-β-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM.     

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P2₁/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO₂ and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO₂/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO₂ group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.     

Extraction of Phenolic Compounds from Fresh Apple Pomace by Different Non-Conventional Techniques

Red Delicious apple pomace was produced at laboratory scale with a domestic blender and different non-conventional extraction techniques were performed to isolate phenolic compounds, such as ultrasound-assisted extraction (UAE), ultraturrax extraction (UTE), accelerated solvent extraction (ASE) and pulsed electric field (PEF) extraction pre-treatment. Total phenolic content (TPC) was determined by Folin–Ciocalteu assay. Phloridzin, the main phenolic compound in apples, was determined by chromatographic analysis Q-TOF-LC/MS. The results obtained with these techniques were compared in order to identify the most efficient method to recover polyphenols. The highest value of TPC (1062.92 ± 59.80 µg GAE/g fresh apple pomace) was obtained when UAE was performed with EtOH:H₂O (50:50, v/v), while ASE with EtOH:H₂O (30:70, v/v) at 40 °C and 50% of flush was the most efficient technique in the recovery of phloridzin. The concentration of the main phenolic compounds ranged from 385.84 to 650.56 µg/g fresh apple pomace. The obtained results confirm that apple pomace represents an interesti-ng by-product, due to the presence of phenolic compounds. In particular, phloridzin could be considered a biomarker to determine the quality of numerous apple products. Therefore, this research could be a good starting point to develop a value-added product such as a functional food or nutraceutical.     

Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified α_vβ₃ and α₅β₁ receptors using biotinylated vitronectin (α_vβ₃) and fibronectin (α₅β₁) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for α_vβ₃ over α₅β₁. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin α_vβ₃). The two RGD ligands showed IC₅₀ values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC₅₀ value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the α_Vβ₃ integrin active site, provided a rationale for the behavior of these ligands toward the receptor.     

Design and Development of D‒α‒Tocopheryl Polyethylene Glycol Succinate‒block‒Poly(ε-Caprolactone) (TPGS−b−PCL) Nanocarriers for Solubilization and Controlled Release of Paclitaxel

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1–5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using ¹H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS₂₀₀₀-b-PCL₄₀₀₀, TPGS₃₅₀₀-b-PCL₇₀₀₀, and TPGS₅₀₀₀-b-PCL₁₅₀₀₀ micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS₅₀₀₀-b-PCL₁₅₀₀₀. Of the abovementioned micellar formulations, TPGS₅₀₀₀-b-PCL₁₅₀₀₀ showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS₅₀₀₀-b-PCL₁₅₀₀₀ micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel^®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX.     

New Halogenated Compounds from Halimeda macroloba Seaweed with Potential Inhibitory Activity against Malaria

Malaria is one of the most important infectious diseases worldwide. The causative of the most severe forms of malaria, Plasmodium falciparum, has developed resistances against all the available antimalarial drugs. In the present study, the phytochemical investigation of the green seaweed Halimeda macroloba has afforded two new compounds 1–2, along with 4 known ones 3–6. The structures of the compounds had been confirmed using 1& 2D-NMR and HRESIMS analyses. Extensive machine-learning-supported virtual-screening suggested cytochrome-C enzyme as a potential target for compound 2. Docking, absolute-binding-free-energy (ΔG_binding) and molecular-dynamics-simulation (MDS) of compound 2 revealed the strong binding interaction of this compound with cytochrome-C. In vitro testing for crude extract and isolated compounds revealed the potential in vitro inhibitory activity of both extract and compound 2 against P. falciparum. The crude extract was able to inhibit the parasite growth with an IC₅₀ value of 1.8 ± 0.35 µg/mL. Compound 2 also showed good inhibitory activity with an IC₅₀ value of 3.2 ± 0.23 µg/mL. Meanwhile, compound 6 showed moderate inhibitory activity with an IC₅₀ value of 19.3 ± 0.51 µg/mL. Accordingly, the scaffold of compound 2 can be considered as a good lead compound for the future development of new antimalarial agents.     

Tuning Photodynamic Properties of BODIPY Dyes,Porphyrins’ Little Sisters

The photodynamic properties of a series of non-halogenated, dibrominated and diiodinated BODIPYs with a phthalimido or amino end modification on the phenoxypentyl and phenoxyoctyl linker in the meso position were investigated. Halogen substitution substantially increased the singlet oxygen production based on the heavy atom effect. This increase was accompanied by a higher photodynamic activity against skin melanoma cancer cells SK-MEL-28, with the best compound reaching an EC₅₀ = 0.052 ± 0.01 µM upon light activation. The dark toxicity (toxicity without light activation) of all studied dyes was not detected up to the solubility limit in cell culture medium (10 µM). All studied BODIPY derivatives were predominantly found in adiposomes (lipid droplets) with further lower signals colocalized in either endolysosomal vesicles or the endoplasmic reticulum. A detailed investigation of cell death indicated that the compounds act primarily through the induction of apoptosis. In conclusion, halogenation in the 2,6 position of BODIPY dyes is crucial for the efficient photodynamic activity of these photosensitizers.     

Roseabol A,a New Peptaibol from the Fungus Clonostachys rosea

A new 11 amino acid linear peptide named roseabol A (1) and the known compound 13-oxo-trans-9,10-epoxy-11(E)-octadecenoic acid (2) were isolated from the fungus Clonostachys rosea. Combined NMR and MS analysis revealed that roseabol A (1) contained amino acid residues characteristic of the peptaibol family of peptides such as isovaline, α-aminoisobutyric acid, hydroxyproline, leucinol, and an N-terminal isovaleric acid moiety. The amino acid sequence was established by a combination of NMR studies and tandem MS fragmentation analyses, and the absolute configurations of the constituent amino acids of 1 were determined by the advanced Marfey’s method. Compound 2 showed inhibitory activity against Merkel cell carcinoma, a rare and difficult-to-treat type of skin cancer, with an IC₅₀ value of 16.5 μM.     

Preparation and Properties of Cyclodextrin Inclusion Complexes of Hyperoside

In order to improve the aqueous solubility and enhance the bioavailability of Hyperoside (Hyp), three inclusion complexes (ICs) of Hyp with 2-hydroxypropyl-β-cyclodextrin (2H-β-CD), β-cyclodextrin (β-CD), and methyl-β-cyclodextrin (M-β-CD) were prepared using the ultrasonic method. The characterization of the inclusion complexes (ICs) was achieved using Fourier-transform infrared spectroscopy (FTIR), scanning electronic microscopy (SEM), X-ray powder diffraction (XRPD), thin-layer chromatography (TLC), and ¹H nuclear magnetic resonance (¹H NMR). The effects of the ICs on the solubility and antioxidant activity of Hyp were investigated. A Job’s plot revealed that the Hyp formed ICs with three kinds of cyclodextrin (CD), all at a 1:1 stoichiometric ratio. The FTIR, SEM, XRPD, TLC, and ¹H NMR results confirmed the formation of inclusion complexes. The water solubility of the IC of Hyp with 2-hydroxypropyl-β-cyclodextrin was enhanced 9-fold compared to the solubility of the original Hyp. The antioxidant activity tests showed that the inclusion complexes had higher antioxidant activities compared to free Hyp in vitro and the H₂O₂–RAW264.7 cell model. Therefore, encapsulation with CDs can not only improve Hyp’s water solubility but can also enhance its biological activity, which provides useful information for the potential application of complexation with Hyp in a clinical context.     

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.     

Synthesis,spectroscopic, thermal,crystal structure properties and characterization of new Hofmann-type-like clathrates with 4-aminopyridine and water

In this study, synthesis of two new heteronuclear tetracyanonickelate(II) clathrates based on 4-aminopyridine (4AP) and guest water (H₂O) molecule and investigation of their structural properties were reported. These clathrates were characterized by using vibration spectroscopy, elemental, thermal analysis and single crystal X-ray diffraction (SC-XRD) techniques. Examining the elemental and spectral data of these clathrates, it was observed that the formulas [Zn(II)(4AP)₂Ni(µ-CN)₂(CN)₂]·6H₂O and [Cu(II)(4AP)₄Ni(µ-CN)₂(CN)₂]·H₂O were defined their structures. General information about the structural properties of these clathrates in single crystal form has been obtained by considering the changes in the characteristic peaks of the cyanide group and the 4AP that formed them. The thermal behaviors of these clathrates were obtained by examining the temperature-dependent changes of their masses. The magnetic susceptibilities of these clathrates in single crystal form were measured with a Gouy balance. According to the data obtained using SC-XRD technique, the heterometallic [Zn(II)(4AP)₂Ni(µ-CN)₂(CN)₂]·6H₂O compound has Cmcm and the heterometallic [Cu(II)(4AP)₄Ni(µ-CN)₂(CN)₂]·H₂O compound has crystal structures in the C2 / c space group.     

Synthesis of 2-Aminopyrimidine Derivatives and Their Evaluation as β-Glucuronidase Inhibitors: In Vitro and In Silico Studies

Currently the discovery and development of potent β-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives 1–27 were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds 1–27 were then evaluated for their β-glucuronidase inhibitory activity, and among them, compound 24 (IC₅₀ = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and β-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent β-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products.     

Antiprotozoal and Antibacterial Activity of Ravenelin,a Xanthone Isolated from the Endophytic Fungus Exserohilum rostratum

The natural compound ravenelin was isolated from the biomass extracts of Exserohilum rostratum fungus, and its antimicrobial, antiplasmodial, and trypanocidal activities were evaluated. Ravenelin was isolated by column chromatography and HPLC and identified by NMR and MS. The susceptibility of Gram-positive and Gram-negative bacteria strains to ravenelin was determined by microbroth dilution assay. Cytotoxicity was evaluated in hepatocarcinoma cells (HepG2) and BALB/c peritoneal macrophages by using MTT. SYBR Green I-based assay was used in the asexual stages of Plasmodium falciparum. Trypanocidal activity was tested against the epimastigote and intracellular amastigote forms of Trypanosoma cruzi. Ravenelin was active against Gram-positive bacteria strains, with emphasis on Bacillus subtilis (MIC value of 7.5 µM). Ravenelin’s antiparasitic activities were assessed against both the epimastigote (IC₅₀ value of 5 ± 1 µM) and the intracellular amastigote forms of T. cruzi (IC₅₀ value of 9 ± 2 µM), as well as against P. falciparum (IC₅₀ value of 3.4 ± 0.4 µM). Ravenelin showed low cytotoxic effects on both HepG2 (CC₅₀ > 50 µM) and peritoneal macrophage (CC₅₀ = 185 ± 1 µM) cells with attractive selectivity for the parasites (SI values > 15). These findings indicate that ravenelin is a natural compound with both antibacterial and antiparasitic activities, and considerable selectivity indexes. Therefore, ravenelin is an attractive candidate for hit-to-lead development.     

Polycyclic aromatic hydrocarbon-substituted push–pull chromophores: an investigation of optoelectronic and nonlinear optical properties using experimental and theoretical approaches

A series of new push–pull chromophores were synthesized in moderate to very high yields (65%–97%) by treating TCNE and TCNQ with alkynes substituted by electron-rich diethylaniline and polycyclic aromatic hydrocarbons. Some of the chromophores exhibit strong intramolecular charge-transfer bands in the near-IR region with λ_max values between 695 and 749 nm. With the help of experimental and theoretical analysis, it is concluded that the trend in λ _max values is affected by PAH substituents sterically, not electronically. Steric constraints led to the increased dihedral angles, reducing conjugation efficiencies. The absorption properties of push-pull compounds have been investigated in solvents possessing different polarities. All chromophores exhibited positive solvatochromism. As an additional proof of efficient charge-transfer in push–pull chromophores, quinoid character (dr) values were predicted using calculated bond lengths. Remarkably, substantial dr values (0.045–0.049) were predicted for donor diethylaniline rings in all compounds. The effects of various polycyclic aromatic hydrocarbons on optical and nonlinear optical properties were also studied by computational methods. Several parameters, such as band gaps, Mulliken electronegativity, chemical hardness and softness, dipole moments, average polarizability, first hyperpolarizability, were predicted for chromophores at the B3LYP/6-31++G(d,p) level of theory. The predicted first hyperpolarizability β_(tot) values vary between 198 to 538 × 10^–30 esu for the reported push–pull chromophores in this study. The highest predicted β_(tot) value in this study is 537.842 × 10^–30 esu, 8150 times larger than the predicted β_(tot) value of benchmark NLO material urea, suggests possible utilization of these chromophores in NLO devices. The charge-transfer character of the synthesized structures was further confirmed by HOMO-LUMO depictions and electrostatic potential maps.     

Design,Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators

The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC₅₀ in the anti-HIV-2 assays (EC₅₀ = 4.86 ± 1.71 μM; CC₅₀ = 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.