Investigating the Effectiveness of Different Porous Nanoparticles as Drug Carriers for Retaining the Photostability of Pinosylvin Derivative.

Pinosylvin monomethyl ether (PsMME) is a natural compound known for its valuable bioactive properties, including antioxidant and anti-inflammatory effects. However, PsMME's susceptibility to photodegradation upon exposure to ultraviolet (UV) radiation poses a significant limitation to its applications in the pharmaceutical field. This study, for the first time, introduces a strategy to enhance the photostability of PsMME by employing various nanoformulations. We utilized mesoporous silica nanoparticles (MSNs) coated with polydopamine via a poly(ethylene imine) layer (PDA-PEI-MSNs), thermally carbonized porous silicon nanoparticles (TCPSi), and pure mesoporous polydopamine nanoparticles (MPDA). All these nanocarriers exhibit unique characteristics, including the potential for shielding the drug from UV light, which makes them promising for enhancing the photostability of loaded drugs. Here, these three nanoparticles were synthesized and their morphological and physicochemical properties, including size and ζ-potential, were characterized. They were subsequently loaded with PsMME, and the release profiles and kinetics of all three nanoformulations were determined. To assess their photoprotection ability, we employed gas chromatography with a flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS) to assess the recovery percentage of loaded PsMME before and after UV exposure for each nanoformulation. Our findings reveal that MPDA exhibits the highest protection ability, with a remarkable 90% protection against UV light on average. This positions MPDA as an ideal carrier for PsMME, and by extension, potentially for other photolabile drugs as well. As a final confirmation of its suitability as a drug nanocarrier, we conducted cytotoxicity evaluations of PsMME-loaded MPDA, demonstrating dose-dependent drug toxicity for this formulation.

In vivo Analgesic Activity of New N-arylphthalimides Derivatives in Mice.

BACKGROUND: A series of phthalimides related to thalidomide have been studied for analgesic activity in the formalin test. The formalin test was performed in mice in a nociceptive pattern to evaluate analgesic activity. METHODS: In this study, nine derivatives of phthalimides were evaluated in terms of exerting analgesic effects in mice. They exerted significant analgesic effects compared to indomethacin and negative control. These compounds were synthesized and characterized by TLC, followed by IR and H1NMR in the previous studies. Two distinct periods of high licking activity were used to analyze both acute and chronic pain. All compounds were compared with indomethacin and carbamazepine as positive control and vehicle as a negative control. RESULTS: All of the tested compounds exhibited significant analgesic activity in both the first and second phases of the test compared to the control group (DMSO), although they did not show more activity than the reference drug (indomethacin) but were comparable to indomethacin. CONCLUSION: This information may be useful in the development of a more potent phthalimide as an analgesic agent that acts as a sodium channel blocker and COX inhibitor.

Stilbenoid compounds inhibit NF-κB-mediated inflammatory responses in the Drosophila intestine.

Introduction: Stilbenoid compounds have been described to have anti-inflammatory properties in animal models in vivo, and have been shown to inhibit Ca2+-influx through the transient receptor potential ankyrin 1 (TrpA1). Methods: To study how stilbenoid compounds affect inflammatory signaling in vivo, we have utilized the fruit fly, Drosophila melanogaster, as a model system. To induce intestinal inflammation in the fly, we have fed flies with the intestinal irritant dextran sodium sulphate (DSS). Results: We found that DSS induces severe changes in the bacteriome of the Drosophila intestine, and that this dysbiosis causes activation of the NF-κB transcription factor Relish. We have taken advantage of the DSS-model to study the anti-inflammatory properties of the stilbenoid compounds pinosylvin (PS) and pinosylvin monomethyl ether (PSMME). With the help of in vivo approaches, we have identified PS and PSMME to be transient receptor ankyrin 1 (TrpA1)-dependent antagonists of NF-κB-mediated intestinal immune responses in Drosophila. We have also computationally predicted the putative antagonist binding sites of these compounds at Drosophila TrpA1. Discussion: Taken together, we show that the stilbenoids PS and PSMME have anti-inflammatory properties in vivo in the intestine and can be used to alleviate chemically induced intestinal inflammation in Drosophila.

Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore-based virtual screening approach.

Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca2+ mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC50 values ranging from 10.64 to 64.56 µM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.

2, 5-Disubstituted Phthalimides: Design, Synthesis and Anticonvulsant Activity in scPTZ and MES Models.

INTRODUCTION: In this study, fifteen new 2,5-disubstituted analgouges of phthalimide were designed and synthesized using the appropriate synthetic route to evaluate anticonvulsant activity against the Maximal Electroshock (MES) and subcutaneous Pentylenetetrazole (scPTZ) compare to phenytoin as a positive control. The structures of the synthesized compounds were confirmed by FTIR, H-NMR, C-NMR and MASS spectroscopy. METHODS: All the tested compounds were found to be effective in the PTZ model at dose of 60 mg/kg and most of the compounds showed protection against MES test indicative of their ability to inhibit the seizure spread at all dose ranges. Compound 3 illustrated the best efficacy among all compounds and showed more potency than phenytoin in clonic seizure and was potent as phenytoin in tonic seizure. RESULTS & DISCUSSION: Using a model of the Na channel, these derivatives were docked in the active site. Docking studies displayed that all synthesized compounds have more negative binding energy compare to reference drug and inhibition-constant less than phenytoin that means they can block the receptor more efficiently and usually form hydrophobic interactions or hydrogen bond interaction frequently with the domains I, II, III and rarely with domain IV.

Docking, Synthesis and Anticonvulsant Activity of N-substituted Isoindoline-1,3-dione.

A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and H1NMR. In-vivo screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/Kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock 4.2 program. Docking study has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel.

Docking studies of phthalimide pharmacophore as a sodium channel blocker.

OBJECTIVE(S): Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of 19 compounds of phthalimide pharmacophore possessing a variety of substituents (NO2, NH2, Me, Cl, COOH, MeO) at 2-, 3-, and 4- position of the N-phenyl ring and N-(3-amino-2-methylphenyl) succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels. Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM3 force field. Total energy gradient calculated as a root mean square (RMS) value, until the RMS gradient was 0.01 kcal mol(-1). Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK4.2 program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S6 residues of NaV1.2 through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. CONCLUSION: These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently.