Exploring the sedative properties of natural molecules from hop cones (Humulus lupulus) as promising natural anxiolytics through GABA receptors and the human serotonin transporter.

This research work aimed to identify the main components that are responsible for the sedative properties of hop cones and allocate their targets. This investigation was performed through molecular docking, molecular dynamic simulations, root mean square fluctuation (RMSF) analysis, and DFT calculation techniques. The tested compounds from Humulus lupulus were compared to diazepam and paroxetine. Molecular docking showed that two-thirds of the compounds had a good affinity to gamma-aminobutyric acid (GABA), outperforming diazepam, while only three surpassed paroxetine on the SERT. Compounds 3,5-dihydroxy-4,6,6-tris(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (5) and (S,E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (15) showed stable binding and favorable energy parameters, indicating their potential for targeting GABA receptors and the SERT. This study provides a basis for future clinical research on these promising compounds.

Unveiling meta-Alkyloxy/-Silyloxy-Substituted N-Aryl PNP Ligands for Efficient Cr-Catalyzed Ethylene Tetramerization.

Novel N-aryl-functionalized PNP ligands (1-4) bearing m-alkyloxy/-silyloxy substituents were prepared and evaluated for chromium-catalyzed ethylene oligomerization using MMAO-3A as an activator. The selected Cr/PNP system under optimized condition exhibited high 1-octene-selective (up to 70 wt %) ethylene tetramerization at a remarkable rate (over 3000 kg gCr-1 h-1). More importantly, the undesirable polyethylene selectivity was restricted to a minimum level of ∼1-2 wt % for pre-catalysts derived with ligands 1 and 2. Employing chlorobenzene as a reaction medium yielded best productivity in conjunction to the total α-olefin (1-C6 + 1-C8) selectivity (∼88 wt %). N-aryl PNP ligands (3 and 4) incorporating m-silyloxy substituents in the phenyl ring exhibited relatively poorer tetramerization performance while yielding higher PE fraction as compared to their m-alkyloxy derivatives. A detailed molecular structure of the best-performing pre-catalyst 1-Cr was established by single-crystal X-ray diffraction analysis. The stability of 1/Cr-based catalyst system was investigated for a reaction time of up to 2 h under optimized condition.

Design and synthesis of novel cytotoxic fluoroquinolone analogs through topoisomerase inhibition, cell cycle arrest, and apoptosis.

To exploit the advantageous properties of approved drugs to hasten anticancer drug discovery, we designed and synthesized a series of fluoroquinolone (FQ) analogs via functionalization of the acid hydrazides of moxifloxacin, ofloxacin, and ciprofloxacin. Under the NCI-60 Human Tumor Cell Line Screening Assay, (IIIf) was the most potent among moxifloxacin derivatives, whereas (VIb) was the only ofloxacin derivative with significant effects and ciprofloxacin derivatives were devoid of activity. (IIIf) and (VIb) were further selected for five-dose evaluation, where they showed potent growth inhibition with a mean GI50 of 1.78 and 1.45 µM, respectively. (VIb) elicited a more potent effect reaching sub-micromolar level on many cell lines, including MDA-MB-468 and MCF-7 breast cancer cell lines (GI50 = 0.41 and 0.42 µM, respectively), NSCLC cell line HOP-92 (GI50 = 0.50 µM) and CNS cell lines SNB-19 and U-251 (GI50 = 0.51 and 0.61 µM, respectively). (IIIf) and (VIb) arrested MCF-7 cells at G1/S and G1, respectively, and induced apoptosis mainly through the intrinsic pathway as shown by the increased ratio of Bax/Bcl-2 and caspase-9 with a lesser activation of the extrinsic pathway through caspase-8. Both compounds inhibited topoisomerase (Topo) with preferential activity on type II over type I and (VIb) was marginally more potent than (IIIf). Docking study suggests that (IIIf) and (VIb) bind differently to Topo II compared to etoposide. (IIIf) and (VIb) possess high potential for oral absorption, low CNS permeability and low binding to plasma proteins as suggested by in silico ADME calculations. Collectively, (IIIf) and (VIb) represent excellent lead molecules for the development of cytotoxic agents from quinolone scaffolds.

Chemical and Biological Review of Endophytic Fungi Associated with Morus sp. (Moraceae) and In Silico Study of Their Antidiabetic Potential.

The chronic nature of diabetes mellitus motivates the quest for novel agents to improve its management. The scarcity and prior uncontrolled utilization of medicinal plants have encouraged researchers to seek new sources of promising compounds. Recently, endophytes have presented as eco-friendly leading sources for bioactive metabolites. This article reviewed the endophytic fungi associated with Morus species and their isolated compounds, in addition to the biological activities tested on their extracts and chemical constituents. The relevant literature was collected from the years 2008-2022 from PubMed and Web of Science databases. Notably, no antidiabetic activity was reported for any of the Morus-associated endophytic fungal extracts or their twenty-one previously isolated compounds. This encouraged us to perform an in silico study on the previously isolated compounds to explore their possible antidiabetic potential. Furthermore, pharmacokinetic and dynamic stability studies were performed on these compounds. Upon molecular docking, Colletotrichalactone A (14) showed a promising antidiabetic activity due to the inhibition of the α-amylase local target and the human sodium-glucose cotransporter 2 (hSGT2) systemic target with safe pharmacokinetic features. These results provide an in silico interpretation of the possible anti-diabetic potential of Morus endophytic metabolites, yet further study is required.

A rational approach towards selective ethylene oligomerization via PNP-ligand design with an N-triptycene functionality.

Novel PNP ligands bearing an N-triptycene backbone were developed and evaluated for selective ethylene oligomerization. Upon activation with MMAO-3A, the pre-catalyst mixture containing Cr(acac)3/ligand efficiently promotes ethylene tetramerization with remarkably high productivities (up to 1733 kg gCr-1 h-1) and C8 olefin selectivities (up to 74.1 wt%). More importantly, ligands with a PNP moiety connecting at the 1- or 1,4-position of the triptycene molecule could achieve exceptionally high alpha (1-C6 + 1-C8) selectivities, exceeding 90 wt%, as a result of high 1-C6 purity (>90 wt%) in the C6 fraction. Based on comparative catalytic studies employing various PNP ligands with or without an N-triptycene backbone, we illustrate the fact that a rational design of PNP ligands with an optimum degree of steric profile around the N-center could provide C6 cyclics controlled highly α-selective ethylene oligomerization.

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management.

Keratoconus (KC) is a serious disease that can affect people of any race or nationality, although the exact etiology and pathogenic mechanism are still unknown. In this study, thirty-two FDA-approved ophthalmic drugs were exposed to virtual screening using docking studies against both the MMP-2 and MMP-9 proteins to find the most promising inhibitors as a proposed computational mechanism to treat keratoconus. Matrix metalloproteinases (MMPs) are zinc-dependent proteases, and MMP inhibitors (MMPIs) are usually designed to interact with zinc ion in the catalytic (CAT) domain, thus interfering with enzymatic activity. In our research work, the FDA-approved ophthalmic medications will be investigated as MMPIs, to explore if they can be repurposed for KC treatment. The obtained findings of the docking study suggest that atenolol and ampicillin are able to accommodate into the active sites of MMP-2 and MMP-9. Additionally, both exhibited binding modes similar to inhibitors used as references, with an ability to bind to the zinc of the CAT. Molecular dynamic simulations and the MM-GBSA binding free-energy calculations revealed their stable binding over the course of 50 ns. An additional pharmacophoric study was carried out on MMP-9 (PDB ID: 1GKC) using the co-crystallized ligand as a reference for the future design and screening of the MMP-9 inhibitors. These promising results open the door to further biological research to confirm such theoretical results.

Identification of Some Promising Heterocycles Useful in Treatment of Allergic Rhinitis: Virtual Screening, Pharmacophore Mapping, Molecular Docking, and Molecular Dynamics.

Rhinitis is an allergic disease that causes troubles and restlessness for patients. In this research work we will focus on finding promising organic molecules with potential ability to target histamine receptor with no sedative side effect. Phalazines and their isosteres, pyrimidines and pyridines have been reported to target H1 receptors, for this reason we have searched for library of these basic scaffolds, this library which has 184 organic molecules will be subjected for further explorations through computer aided drug design techniques. Swiss ADMET will be used to gather these compounds in clusters. Cluster with low potential to penetrate BBB is selected for virtual screening through pharmacophore model. Then molecular docking that revealed the stability of the complex formed between the investigated molecules and H1 receptor. ADMET profile showed three compounds (XVIII), (XX), and (XXI) with no toxicity on liver and no effect on CYP2D6, these three compounds were subjected to molecular dynamic simulations and compound (XVIII) showed the most stable complex with the target protein (H1). Finally, we can say this work helped us to find new compounds with promising potential to target H1 without ability to penetrate BBB, so they can be used as useful candidates in treatment of rhinitis and deserve to be subjected for preclinical and clinical investigations. Supplementary Information: The online version contains supplementary material available at 10.1134/S1068162022330019.

Computer-assisted catalyst development via automated modelling of conformationally complex molecules: application to diphosphinoamine ligands.

Simulation of conformationally complicated molecules requires multiple levels of theory to obtain accurate thermodynamics, requiring significant researcher time to implement. We automate this workflow using all open-source code (XTBDFT) and apply it toward a practical challenge: diphosphinoamine (PNP) ligands used for ethylene tetramerization catalysis may isomerize (with deleterious effects) to iminobisphosphines (PPNs), and a computational method to evaluate PNP ligand candidates would save significant experimental effort. We use XTBDFT to calculate the thermodynamic stability of a wide range of conformationally complex PNP ligands against isomeriation to PPN (ΔGPPN), and establish a strong correlation between ΔGPPN and catalyst performance. Finally, we apply our method to screen novel PNP candidates, saving significant time by ruling out candidates with non-trivial synthetic routes and poor expected catalytic performance.

Formation and characterization of high surface area thermally stabilized titania/silica composite materials via hydrolysis of titanium(IV) tetra-isopropoxide in sols of spherical silica particles.

A direct synthetic route leading to titania particles dispersed on nonporous spherical silica particles has been investigated; 5, 10, and 20% (w/w) titania/silica sols mixtures were achieved via hydrolyzation of titanium tetra-isopropxide solution in the mother liquor of a freshly prepared sol of spherical silica particles (Stöber particles). Titania/silica materials were produced by subsequent drying and calcination of the xerogels so obtained for 3 h at 400 and 600 degrees C. The materials were investigated by means of thermal analyses (TGA and DSC), FT-IR, N(2) gas adsorption-desorption, powder X-ray diffraction (XRD), and transmission electron microscopy (TEM). In spite of the low surface area (13.1 m(2)/g) of the pure spherical silica particles calcined at 400 degrees C, high surface area and mesoporous texture titania/silica materials were obtained (e.g., S(BET) ca. 293 m(2)/g for the 10% titania/silica calcined at 400 degrees C). Moreover, the materials were shown to be amorphous toward XRD up to 600 degrees C, while reasonable surface areas were preserved. It has been concluded that dispersion of titania particles onto the surface of the nonporous spherical silica particles increase their roughness, therefore leading to composite materials of less firm packing and mesoporosity.