•11 compounds were isolated from the stems of Actinidia polygama.•2α,3α,24-trihydroxyurs-12-en-28-oic acid (4) strongly inhibited β-glucuronidase.•Compound 4 acts as a non-competitive inhibitor of ...β-glucuronidase.•Molecular docking and dynamics revealed the interaction and stability of compound 4 with the binding site.
Actinidia polygama, well-known for its traditional medicinal properties, has garnered significant attention due to its distinctive chemical composition. In this study, we isolated and structurally elucidated 11 known compounds, including a monoterpene glycoside (1), eight triterpenoids (2–9), and two lignan glycosides (10 and 11), from A. polygama stems. Notably, the inhibitory activity of these compounds on β-glucuronidase activity was evaluated for the first time. Our results show that 2α,3α,24-trihydroxyurs-12-en-28-oic acid (4), strongly inhibited β-glucuronidase (IC50 = 14.36 ± 0.42 μM) to a degree much higher than that of the positive control (d-saccharic acid 1,4-lactone, DSA; IC50 = 16.30 ± 0.21 μM). Furthermore, the results of an enzyme kinetics analysis indicate that compound 4 acts as a non-competitive inhibitor of β-glucuronidase. Finally, the findings from molecular docking and molecular dynamics simulations confirmed the inhibition mode of compound 4, its interaction with the allosteric site of β-glucuronidase, and the stability of the complex in the bound state.
•Intrinsic clearances of twelve pharmaceuticals in rainbow trout S9 fractions assessed.•Five substances were measurably cleared in RT-S9, four of them via cytochrome P450.•Five substances were also ...inhibitors of EROD and four of BFCOD activity in RT-S9.•In mixtures, P450 inhibition reduced the clearances of 4 out of 5 pharmaceuticals.•The results shed light on the mechanisms of the combined effects of pharmaceuticals.
Residues of human pharmaceuticals are widely detected in surface waters and can be taken up by and bioaccumulate in aquatic organisms, especially fish. One of the key challenges in assessing the bioaccumulation potential of ionizable organic compounds, such as the pharmaceuticals, is the lack of empirical data for biotransformation. In the present study, we assessed the in vitro intrinsic clearances (CLINT) of twelve pharmaceuticals, individually and some additionally as mixtures, in rainbow trout (Oncorhynchus mykiss) liver S9 fractions (RT-S9) adhering to the OECD test guidance 319B. The test substances included four anti-inflammatory agents (diclofenac, ibuprofen, ketoprofen, naproxen), seven antidepressants/antipsychotics (citalopram, haloperidol, levomepromazine, mirtazapine, risperidone, sertraline, venlafaxine) and the O-desmethyl metabolite of venlafaxine. Quantifiable intrinsic clearances were detected for diclofenac, ibuprofen, naproxen, levomepromazine, and sertraline. Apart from diclofenac, the in vitro clearances of the other four pharmaceuticals were shown to be critically dependent on the cytochrome P450 (CYP) metabolism. Therefore, we also determined the half-maximal inhibitory concentrations (IC50) of the same twelve pharmaceuticals toward CYP1A-like (7-ethoxyresorufin-O-deethylation, EROD) and CYP3A-like (benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylation, BFCOD) activities in RT-S9 using IC50 shift assay. As a result, levomepromazine and sertraline were identified as the most potent inhibitors of both EROD and BFCOD activity (unbound IC50 < 10 µM each), followed by citalopram and haloperidol (10 µM < IC50 < 100 µM). Additionally, mirtazapine was a selective EROD inhibitor (IC50 ∼ 30 µM). The inhibitory impacts of haloperidol and sertraline were indicatively time dependent. Finally, we carried out intrinsic clearance assays with mixtures of diclofenac, ibuprofen, naproxen, levomepromazine, and sertraline to examine the impacts of EROD and BFCOD inhibitions on their in vitro CLINT in RT-S9. Our in vitro data suggests that the intrinsic clearances of ibuprofen, levomepromazine, and sertraline in rainbow trout can be significantly reduced as the result of P450 inhibition by pharmaceutical mixtures, whereas the clearances of diclofenac and naproxen are less impacted.
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•Novel cobalt phthalocyanine (2) and its graphene oxide (GO) composites (2a-2f).•Examination of their impact on several metabolic enzymes, including α-Glycosidase (α-Gly) and ...Butyrylcholinesterase (BChE).•Pharmacodynamic studies, the model form of novel compounds, their structural orientations in the active sites of enzymes.•Investigation of their binding interaction mechanism, and their drug potential.
This study produced novel cobalt phthalocyanine (CoPc) (2) and its graphene oxide (GO) composites (2a-2f) and examined their impact on several metabolic enzymes, including α-glycosidase (α-Gly), achetylcholinesterase (AChE) and butyrylcholinesterase (BChE). IC50 values showed that when compared to conventional inhibitors, all the compounds demonstrated strong inhibitory effects against all targets. The ranges for the Ki values of the compounds containing the AChE, BChE, and α-glycosidase enzymes were 26.15 ± 3.85–48.26 ± 7.43, 5.46 ± 0.57–10.68 ± 0.78, and 2.20 ± 0.11–22.41 ± 2.60 nM, in that order. In addition, pharmacodynamic studies, the model form of new CoPc/GO composites, their structural orientations in the active sites of AChE, BChE and α-Gly enzymes, respectively, their binding interaction mechanism, and even their drug potential were investigated. The relevant compound (CoPc/GO) shows a binding energy trend of −12.40, −12.30 and −12.10 kcal/mol to α-Gly, AChE and BChE enzymes, respectively. In addition, it was determined that the compounds exhibited cytotoxic effects against human breast cancer cells. After more than 20 years of usage, cholinesterase inhibitors (ChEIs) are still a crucial component of the therapy of Alzheimer’s disease (AD). In multiple multicenter, well-controlled trials, only ChEIs have consistently demonstrated efficacy against AD; as a result, they have been widely approved by national regulatory authorities. Even if there have been a lot of ChEI discoveries recently, drug discovery is a continuous process that involves looking for novel strategies and chemotypes.
•A facile single-step methodology has been applied for the re-synthesize of β-amino alcohols (1–3) in accordance.•The our study was to determine the cytotoxic activity of compound 1, 2 and 3 on ...SH-SY5Y and l-929 cell lines.•The working molecules have been optimized on B3LYP, HF, M062X level 3–21 g, 6–31 g, and SDD basis sets.•NMR, UV–vis, and IR spectra of compound 1, 2 and 3 were obtained experimentally and theoretically.•Inhibition properties of these novel derivatives having remarkable biological activities were investigated on activities of acetylcholinesterase (AChE) and α-Glycosidase (α-Gly) enzymes in respect to antidiabetic and anticholinesterase potentials.•Molecular docking calculations were made to compare the biological activities of molecules. And ADME/T calculations were made.
In this study, an efficient single-step method for the preparation of β-amino alcohols (1–3) in aqueous media was applied. The aim was to investigate the cytotoxic activity of Compounds 1, 2 and 3 in neuroblastoma SH-SY5Y cell line and mouse fibroblast l-929 cell lines. Cytotoxic activities of compounds 1, 2 and 3 in this cell lines were also determined by MTT method. Cells were incubated with different concentrations of Compound 3 showed the highest cytotoxic activity in SHY5Y cells at an IC50 dose of 13.01±0.87 µM at 72 h compared to other compounds. Compound 3 was determined to have lower cytotoxic activity in l-929 cells. The chemical activities of the molecules against the B3LYP, HF, M062X level 3–21 g, 6–31 g, and SDD basis set with the Gaussian package program and biologically against the adenosine A(2A) receptor (PDB ID: 3PWH and 5NM4) proteins for neuroblastoma tumors cell with the Maestro Molecular modeling platform by Schrödinger were compared. Both experimental and theoretical NMR, UV–vis, and IR spectra of the studied molecules were compared. ADME/T analysis was performed to examine the drug properties of the molecules. Finally, these assayed for their activities against metabolic enzymes acetylcholinesterase and α-glucosidase. The most potent compounds against AChE were order compounds 3, 2 and 1 with Ki values of 35.88±6.61, 43.75±8.28, and 45.34±3.50 µM against AChE, respectively. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. These inhibitors may be candidates for drug design.
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•Chiral and achiral cyclic seleno- and thiourea compounds were prepared from enetetramines and appropriate Group VI elements.•These ureas were characterized by elemental analysis, IR, ...1H, 13C NMR spectroscopy.•Their inhibition effects on α-glycosidase, BChE and AChE enzymes were investigated.•These compounds were identified as good inhibitors.
A series of chiral and achiral cyclic seleno- and thiourea compounds bearing benzyl groups on N-atoms were prepared from enetetramines and appropriate Group VI elements in good yields. All the synthesized compounds were characterized by elemental analysis, FT-IR, 1H NMR and 13C NMR spectroscopy, and the molecular and crystal structures of (R,R)-4b and (R,R)-5b were confirmed by the single-crystal X-ray diffraction method. These assayed for their activities against metabolic enzymes acetylcholinesterase, butyrylcholinesterase, and α-glycosidase. These selenourea and thiourea derivatives of chiral and achiral enetetramines effectively inhibit AChE and BChE with IC50 values in the range of 3.32–11.36 and 1.47–9.73 µM, respectively. Also, these compounds inhibited α-glycosidase enzyme with IC50 values varying between 1.37 and 8.53 µM. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. Representatively, the most potent compound against α-glycosidase enzyme, (S,S)-5b, was 12-times more potent than standard inhibitor acarbose; 7b and 8a as most potent compounds against cholinesterase enzymes, were around 5 and 13-times more potent than standard inhibitor tacrine against achethylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively.
In this study the synthesis, characterization, crystal structure, electrochemical studies of metal complexes with thiosemicarbazone of glyoxylic acid were performed. Then, inhibition effects of these ...complexes were determined against α-glycosidase, cytosolic carbonic anhydrase I and II isoforms, butyrylcholinesterase and acetylcholinesterase enzymes.
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Cobalt and nickel nitrates form with thiosemicarbazone of glyoxylic acid (H2GAT) complexes of empirical composition Co(C3H4N3O2S)2∙2H2O, Ni(C3H4N3O2S)2∙2H2O and Ni(C3H6N3O2S)2. X-ray diffraction studies have shown that the Co(HGAT)2∙2H2O, Ni(HGAT)2∙2H2O complexes are mononuclear, in which the coordination around the metal is octahedral, made up of two sulfur atoms, two nitrogen atoms and two oxygen atoms from two ligands. By the interaction of NiCl2·H2O with 2-2-(aminothioxomethyl)hydrazinyl acetic acid (H2TAA) instead of the expected the metal thiosemicarbazonate complex with the hydrogenated on the azomethine group ligand was obtained. The redox properties of these compounds were also investigated by voltammetry on Pt in dimethylsulfoxide/tetrabutylammonium perchlorate. These thiosemicarbazone of glyoxylic acid derivatives had effective inhibition against α-glycosidase, cytosolic carbonic anhydrase I and II isoenzymes, butyrylcholinesterase and acetylcholinesterase. Ki values were found as 26.12–36.58 nM for hCA I, 20.73–40.78 nM for hCA II, 184.30–642.18 nM for AChE, 123.67–342.37 nM for BChE, and 14.66–45.62 nM for α-glycosidase.
•New series of hydrazones possessing imidazole hybrids.•Inhibitory activities of all derivatives were evaluated hCA I and hCA II.•Antiproliferative activities of derivatives were evaluated.•Molecular ...modeling was done to acquire insights for the binding interactions and affinities.
A new series of imidazolyl hydrazone derivatives IA (1-12) were prepared from a condensation reaction between indoline-2,3-dione (isatin) and 2-benzylidenehydrazinecarboximidamide derivatives. The structure of compounds was elucidated using various spectral techniques including FTIR, 1H NMR, 13C NMR, and HRMS. The proposed structure of IA-2 was determined by single-crystal X-ray analysis. Synthesized compounds were evaluated for their inhibitory action against carbonic anhydrase I and II isoenzymes (hCA I and hCA II), as well as cytotoxicity activity in a cancer cell line (HT-29) and a healthy cell line (NIH 3T3). Among them, some compounds exhibited remarkable CA inhibitory activities compared to a standard inhibitor with Ki values in the range of 13.434 ± 3.278-522.549 ± 360.720 nM for hCA I (Ki value for standard inhibitor = 271.15 ± 74.620 nM) and 41.108 ± 10.180-271.171 ± 65.293 nM for hCA II (Ki value for standard inhibitor = 113.07 ± 20.980 nM) and significant antiproliferative activity with less toxicity to a health cell line. In addition, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness qualities and ADME/T analysis was carried out to examine the drug properties of the synthesized compounds.
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•Exploring the new synthetic designs of Sulfonamide metal complexes for combined Antimicrobial, Enzyme inhibitory and anti-oxidant properties.•Structural studies of ligands and metal complexes at ...M06/6-311+G(d,p) levels to explore their synthetic mode.•NBO, MESP and NPA analysis at WB97XD/6-311+G(d,p) function.•Third order GRP analysis to establish the experimental vs theoretical consequences.
In this report, new sulfonamide based ligands (L1)-(L3) from 4-amino-N-(pyrimidin-2-yl)benzene-1-sulfonamide are synthesized and branded on the basis of their physical, analytical and spectral (1H & 13C-NMR, MS, FT-IR, UV–Vis) grounds. The ligands reacted with the transition metals (VO2+, Fe2+, Co2+, Ni2+, Cu2+ & Zn2+) to synthesize their complexes (1)-(18). Their structure was considered by their elemental, conductance, magnetic, physical, and spectral (UV–Vis, FT-IR & MS) analysis. The geometry optimization of the compounds was achieved at M06/6-311+G(d,p). The natural bond orbital (NBO) analysis with a WB97XD/6-311+G(d,p) function demonstrated that the inter-molecular charges and the hyper conjugation play a significant role in stabilizing the molecular systems. The orbital band gap explained chemical interactions and the phenomena of charge transfer. The lowest band gap of HOMO/LUMO (0.78 eV) is shown for compound (l3), while the highest gap of 1.47 eV is found for ligand (L3). The global parameters of reactivity (GRP) have been investigated with (L2) having higher hardness (2.384 eV) and (17) with higher (2.27 eV) softness (S). The in vitro screening results for their antibacterial activity revealed the compound (5) with the highest activity (31 mm) against Streptococcus aureus while the antifungal activity ranged between 11-28 mm with the compound (12) having the highest one for Aspergillus niger. The enzyme inhibition activity (%) against α-Amylase, Protease, Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) with highest (75±0.11; IC50: 66±0.11µL, 73±0.11; IC50: 68±0.10 µL, 75±0.12; IC50: 66±0.11 µL and 71±0.12; IC50: 70±0.08 µL) activity for compounds (16), (18), (17), respectively. The antioxidant action was explored by operating several in vitro assays: scavenging activity against DPPH radical, reducing power against ferric oxidation and total phenols as Gallic acid equivalents. Results indicated that the compound (7) has offered the highest (67.02 ± 0.09) DPPH activity. The results revealed all the compounds to be more biologically active than free ligands. These results also indicated that the meal complexes may be considered for further drug design endeavors.
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