Ligand-Based Drug Design of Genipin Derivatives with Cytotoxic Activity against HeLa Cell Line: A Structural and Theoretical Study.

Cervical cancer is a malignant neoplastic disease, mainly associated to HPV infection, with high mortality rates. Among natural products, iridoids have shown different biological activities, including cytotoxic and antitumor effects, in different cancer cell types. Geniposide and its aglycone Genipin have been assessed against different types of cancer. In this work, both iridoids were evaluated against HeLa and three different cervical cancer cell lines. Furthermore, we performed a SAR analysis incorporating 13 iridoids with a high structural similarity to Geniposide and Genipin, also tested in the HeLa cell line and at the same treatment time. Derived from this analysis, we found that the dipole moment (magnitude and direction) is key for their cytotoxic activity in the HeLa cell line. Then, we proceeded to the ligand-based design of new Genipin derivatives through a QSAR model (R2 = 87.95 and Q2 = 62.33) that incorporates different quantum mechanic molecular descriptor types (ρ, ΔPSA, ∆Polarizability2, and logS). Derived from the ligand-based design, we observed that the presence of an aldehyde or a hydroxymethyl in C4, hydroxyls in C1, C6, and C8, and the lack of the double bond in C7-C8 increased the predicted biological activity of the iridoids. Finally, ten simple iridoids (D9, D107, D35, D36, D55, D56, D58, D60, D61, and D62) are proposed as potential cytotoxic agents against the HeLa cell line based on their predicted IC50 value and electrostatic features.

A Computational Method for the Binding Mode Prediction of COX-1 and COX-2 Inhibitors: Analyzing the Union of Coxibs, Oxicams, Propionic and Acetic Acids.

Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce a novel method-based on computational molecular docking-that could aid in the structure-based design of new compounds or the description of the anti-inflammatory activity of already-tested compounds. For this, we used eight crystal complexes (four COX-1 and COX-2 each), and each pair had a specific NSAID: Celecoxib, Meloxicam, Ibuprofen, and Indomethacin. This selection was based on the ligand selectivity towards COX-1 or COX-2 and their binding mode. An interaction profile of each NSAID was compiled to detect the residues that are key for their binding mode, highlighting the interaction made by the Me group. Furthermore, we rigorously validated our models based on structural accuracy (RMSD < 1) and (R2 > 70) using eight NSAIDs and thirteen compounds with IC50 values for each enzyme. Therefore, this model can be used for the binding mode prediction of small and structurally rigid compounds that work as COX inhibitors or the prediction of new compounds that are designed by means of a structure-based approach.

Efficient and Sustainable Bidentate Amines-Functionalized Resins for Removing Ag+, Cu2+, Pb2+, and Fe3+ from Water.

We evaluate the effectiveness of chelating resins (CR) derived from Merrifield resin (MR) and 1,2-phenylenediamine (PDA), 2,2'-dipyridylamine (DPA), and 2-(aminomethyl)pyridine (AMP) as adsorbent dosimeters for Ag+, Cu2+, Fe3+, and Pb2+ cations from water under competitive and noncompetitive conditions. MR-PDA, MR-DPA, and MR-AMP were obtained in a 95-97% yield and characterized by IR, fluorescence, and SEM. The ability of CRs as adsorbents was determined by batch and flow procedures. MR-PDA showed a batch adsorption capacity order of Fe3+ (29.8 mg/g) > Ag+ (2.7 mg/g) > Pb2+ (2.6 mg/g) at pH 3.4. The flow adsorption showed affinity towards the Ag+ cation at pH 7 (18.4 mg/g) and a reusability of 10 cycles. In MR-DPA, the batch adsorption capacity order was Ag+ (9.1 mg/g) > Pb2+ (8.2 mg/g) > Cu2+ (3.5 mg/g) at pH 5. The flow adsorption showed affinity to the Cu2+ cation at pH 5 (2.2 mg/g) and a reuse of five cycles. In MR-AMP, the batch adsorption capacity was Ag+ (17.1 mg/g) at pH 3.4. The flow adsorption showed affinity to the Fe3+ cation at pH 2 (4.3 mg/g) and a reuse of three cycles. The three synthesized and reusable CRs have potential as adsorbents for Ag+, Cu2+, Fe3+, and Pb2+ cations and showed versatility in metal removal for water treatment.

Novel ciprofloxacin and norfloxacin-tetrazole hybrids as potential antibacterial and antiviral agents: Targeting S. aureus topoisomerase and SARS-CoV-2-MPro.

This study was designed to synthesize hybridizing molecules from ciprofloxacin and norfloxacin by enhancing their biological activity with tetrazoles. The synthesized compounds were investigated in the interaction with the target enzyme of fluoroquinolones (DNA gyrase) and COVID-19 main protease using molecular similarity, molecular docking, and QSAR studies. A QSAR study was carried out to explore the antibacterial activity of our compounds over Staphylococcus aureus a QSAR study, using descriptors obtained from the docking with DNA gyrase, in combination with steric type descriptors, was done obtaining suitable statistical parameters ( R 2 = 87.00 , Q L M O 2 = 71.67 , and Q E X T 2 = 73.49 ) to support our results. The binding interaction of our compounds with CoV-2-Mpro was done by molecular docking and were compared with different covalent and non-covalent inhibitors of this enzyme. For the docking studies we used several crystallographic structures of the CoV-2-Mpro. The interaction energy values and binding mode with several key residues, by our compounds, support the capability of them to be CoV-2-Mpro inhibitors. The characterization of the compounds was completed using FT-IR, 1H-NMR, 13C-NMR, 19F-NMR and HRMS spectroscopic methods. The results showed that compounds 1, 4, 5, 10 and 12 had the potential to be further studied as new antibacterial and antiviral compounds.

DNA-Binding Properties of Bis-N-substituted Tetrandrine Derivatives.

A series of bis-N-substituted tetrandrine derivatives carrying different aromatic substituents attached to both nitrogen atoms of the natural alkaloid were studied with double-stranded model DNAs (dsDNAs) to examine the binding properties and mechanism. Variable-temperature molecular recognition studies using UV-vis and fluorescence techniques revealed the thermodynamic parameters, ΔH, ΔS, and ΔG, showing that the tetrandrine derivatives exhibit high affinity toward dsDNA (K ≈ 105-107 M-1), particularly the bis(methyl)anthraquinone (BAqT) and bis(ethyl)indole compounds (BInT). Viscometry experiments, ethidium displacement assays, and molecular modeling studies enabled elucidation of the possible binding mode, indicating that the compounds exhibit a synergic interaction mode involving intercalation of one of the N-aryl substituents and interaction of the molecular skeleton in the major groove of the dsDNA. Cytotoxicity tests of the derivatives with tumor and nontumor cell lines demonstrated low cytotoxicity of these compounds, with the exception of the bis(methyl)pyrene (BPyrT) derivative, which is significantly more cytotoxic than the remaining derivatives, with IC50 values against the LS-180, A-549, and ARPE-19 cell lines that are similar to natural tetrandrine. Finally, complementary electrochemical characterization studies unveiled good electrochemical stability of the compounds.

Synthesis of 1,4-Biphenyl-triazole Derivatives as Possible 17ß-HSD1 Inhibitors: An in Silico Study.

Triazoles occupy an important position in medicinal chemistry because of their various biological activities. The structural features of 1,2,3-triazoles enable them to act as a bioisostere of different functional groups such as amide, ester, carboxylic acid, and heterocycle, being capable of forming hydrogen bonds and π-π interactions or coordinate metal ions with biological targets. In this work, the synthesis of 1,2,3-triazole derivatives via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is reported. Overexpression of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is often found in breast cancer cells. Molecular similarity and docking analysis were used to evaluate the potential inhibitory activity of 1,2,3-triazoles synthesized over 17ß-HSD1 for the treatment of mammary tumors. Our in silico analysis shows that compounds 4c, 4d, 4f, 4g, and 4j are good molecular scaffold candidates as 17ß-HSD1 inhibitors.

Compuestos bioactivos, actividad antioxidante y perfil de ácidos grasos en aceite de semilla de Mezquite (Prosopis spp) / Bioactive Compounds, Antioxidant Activity and Profile of Fatty Acids in Mesquite Seed Oil (Prosopis spp)

La medicina tradicional y estudios realizados a diferentes especies del género Prosopis, del desierto sonorense, indican que es una fuente para la cualificación de compuestos bioactivos, con poder antioxidante y ácidos grasos (linoleico y linolénico) de la semilla. La actividad biológica, es atribuible a alcaloides, flavonoides, terpenos y compuestos fenólicos, para lo cual, se realizó el perfil fitoquímico en los extractos acuoso, etanólico, hexanico y clorofórmico (mediante técnicas colorimétricas), actividad antioxidante (método: 1,1-difenil-2-picrilhidrazil (DPPH)), fenoles totales (utilizando el reactivo de Folin-Ciocalteau) y perfil de ácidos grasos (cromatografía de gases) de la semilla de Prosopis spp. La extracción del aceite se realizó mediante Soxhlet. Se encontraron saponinas en todos los extractos, mientras que, en el etanólico, hexanico y clorofórmico, terpenos y esteroles. En el extracto etanólico se encontraron quinonas y en el acuoso aminoácidos libres. El valor más alto de la actividad antioxidante de EC50 fue de 3.272,41 ± 5,97, para el extracto etanólico, indicando su potencial como antioxidante. El contenido de fenoles totales, fue hexano> etanol > cloroformo> acuoso (81,95; 119,83; 125,18 y 127,57 mg equivalentes de ácido gálico/g de extracto seco). Los ácidos grasos en mayor proporción fueron los insaturados con 71,41 % (ácido linoleico: 42,68 %; oleico: 28.73 %) y ácidos grasos saturados: ácido palmítico (13.42 %) y estérico (4,73 %). Se concluye que este tipo de extractos presentan metabolitos importantes para la dieta, presentan actividad antioxidante y ácidos grasos esenciales para el organismo(AU)

Traditional medicine and studies with different species of the Prosopis genus, from the Sonoran Desert, is a source for the qualification of bioactive compounds, with antioxidant power and fatty acids (linoleic and linolenic) of the seed. The biological activity is attributable to alkaloids, flavonoids, terpenes and phenolic compounds, for which, the phytochemical profile was performed in the aqueous, ethanolic, hexane and chloroform extracts (using colorimetric techniques), antioxidant activity (method: 1,1-diphenyl-2-picrilhidrazil (DPPH)), total phenols (using the Folin-Ciocalteau reagent) and fatty acid profile (gas chromatography). The oil was extracted using Soxhlet. Saponins were found in all extracts, while, in ethanolic, hexanic and chloroform, terpenes and sterols. In the ethanolic extract quinones were found and in the aqueous free amino acids. The highest value of the antioxidant activity of EC50 was 3,272.41 ± 5.97, for the ethanolic extract, indicating its potential as an antioxidant. The total phenolic content was hexane> ethanol> chloroform> aqueous (81.95, 119.83, 125.18 and 127.57 mg equivalent of gallic acid / g of dry extract). The fatty acids in greater proportion were unsaturated with 71.41 % (linoleic acid: 42.68 %; oleic: 28.73 %) and saturated fatty acids: palmitic acid (13.42 %) and stearic (4.73 %). It is concluded that this type of extracts have important metabolites for the diet, have antioxidant activity and essential fatty acids for the body(AU)

Synthesis, Characterization, and Cu(2+) Coordination Studies of a 3-Hydroxy-4-pyridinone Aza Scorpiand Derivative.

The synthesis, acid-base behavior, and Cu(2+) coordination chemistry of a new ligand (L1) consisting of an azamacrocyclic core appended with a lateral chain containing a 3-hydroxy-2-methyl-4(1H)-pyridinone group have been studied by potentiometry, cyclic voltammetry, and NMR and UV-vis spectroscopy. UV-vis and NMR studies showed that phenolate group was protonated at the highest pH values [log K = 9.72(1)]. Potentiometric studies point out the formation of Cu(2+) complexes of 1:2, 2:2, 4:3, 1:1, and 2:1 Cu(2+)/L1 stoichiometries. UV-vis analysis and electrochemical studies evidence the implication of the pyridinone moieties in the metal coordination of the 1:2 Cu(2+)/L1 complexes. L1 shows a stronger chelating ability than the reference chelating ligand deferiprone. While L1 shows no cytotoxicity in HeLa and ARPE-19 human cell lines (3.1-25.0 µg/mL), it has significant antioxidant activity, as denoted by TEAC assays at physiological pH. The addition of Cu(2+) diminishes the antioxidant activity because of its coordination to the pyridinone moiety phenolic group.

In vitro anti-proliferative activity of Argemone gracilenta and identification of some active components.

BACKGROUND: Cancer is one of the leading causes of death worldwide. Natural products have been regarded as important sources of potential chemotherapeutic agents. In this study, we evaluated the anti-proliferative activity of Argemone gracilenta's methanol extract and its fractions. We identified those compounds of the most active fractions that displayed anti-proliferative activity. METHODS: The anti-proliferative activity on different cancerous cell lines (M12.C3F6, RAW 264.7, HeLa) was evaluated in vitro using the MTT colorimetric method. Identification of the active compounds present in the fractions with the highest activity was achieved by nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS) analyses. RESULTS: Both argemonine and berberine alkaloids, isolated from the ethyl acetate fraction, displayed high anti-proliferative activity with IC50 values of 2.8, 2.5, 12.1, and 2.7, 2.4, 79.5 µg/mL on M12.C3F6, RAW 264.7, and HeLa cancerous cell lines, respectively. No activity was shown on the normal L-929 cell line. From the hexane fraction, a mixture of fatty acids and fatty acid esters of 16 or more carbon atoms with anti-proliferative activity was identified, showing a range of IC50 values of 16.8-24.9, 34.1-35.4, and 67.6-91.8 µg/mL on M12.C3F6, RAW 264.7, and HeLa cancerous cell lines, respectively. On the normal L-929 cell line, this mixture showed a range of IC50 values of 85.1 to 100 µg/mL. CONCLUSION: This is the first study that relates argemonine, berberine, and a mixture of fatty acids and fatty acid esters with the anti-proliferative activity displayed by Argemone gracilenta.