Synthesis, Characterization, and Stability Optimization of Ibuprofen Cocrystals eEploying Various Hydrophilic Polymers.

BACKGROUND: Cocrystals are an efficient way for the delivery of low soluble drugs but when dissolved they rapidly disproportionate. To formulate the cocrystals in tablets, cocrystals must be stabilized. In this study ibuprofen-nicotinamide (IBU-NIC) cocrystals were synthesized initially by slow solvent evaporation and for bulk production by fast solvent evaporation techniques. METHOD: The cocrystals were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectrophotometer (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and optical microscopy. The ibuprofen cocrystals showed greater solubility compared to the parent drug. RESULT: Intrinsic dissolution data was utilized for efficacious screening of tablet formulations. Using hydrophilic polymers at a ratio of 6:1 (polymer to IBU-NIC cocrystal ratio), hydroxypropyl methylcellulose (F1), polyvinylpyrrolidone (PVP) K-30 (F2) and PVP K-90 (F3), three tablet formulations were prepared that stabilized cocrystals during dissolution. The drug release profiles after 60 minutes from formulations F1 (92.30), F2 (98.54), F3 (99.88) were all higher compared to the marketed brand BRUFEN® F, (79.61%) in a simulated intestinal media (p<0.001). CONCLUSION: Significant increase in the dissolution rate of cocrystal was observed with no phase change in all formulations.

One pot synthesis of 5-hydroxyalkylated thiadiazine thiones: Implication in pain management and bactericidal properties.

The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (1-5), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (6-8), 3,5-dipropyl-1, 3, 5-thiadiazine-2-thione (9) and (2-(5-alkyl/aryl-6-thioxo-1, 3, 5-thiadiazine-3-yl) alkyl acetate/benzoate) (10-17) was accomplished via one pot reaction. The structures of the synthesized compounds were characterized through NMR and Mass spectrometry. The anti-nociceptive activity of compounds was performed on BALB/C mice by hot plate method, where compounds 3, 5 (50 µg/kg), and 8 (50, 100 µg/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time of 15, 30, and 60 min, while compounds 6 and 16 (100 µg/kg) exhibited significant effect (P < 0.01, P < 0.05) in latency time interval of 15 and 30 min. Compounds 1, 12-13, and 15 showed moderate activity. Among the tested hits, compounds 5 (17.3 ± 2.2), 11 (16.2 ± 2.1), and 8 (16.1 ± 2.1) showed significant anti-nociceptive potential. Molecular docking studies on the most active anti-nociceptive hits indicated that the activity might be attributed to the ability of the compounds to target µ-opioid receptor (µOR) effectively. Furthermore, compounds 14 and 11 showed anti-bacterial activity against Pseudomonas aeruginosa and MSRA with MIC of 40.97 and 54.77 µg/mL, respectively. In addition, the predicted ADMET profile of 5, 9, and 11 indicates that these molecules follow the drug-likeness criteria, and their activity can be enhanced through structural optimization.

Identification of small molecular inhibitors of SIRT3 by computational and biochemical approaches a potential target of breast cancer.

Sirtuin 3 (SIRT3) belongs to the Sirtuin protein family, which consists of NAD+-dependent lysine deacylase, involved in the regulation of various cellular activities. Dysregulation of SIRT3 activity has been linked to several types of cancer, including breast cancer. Because of its ability to stimulate adaptive metabolic pathways, it can aid in the survival and proliferation of breast cancer cells. Finding new chemical compounds targeted towards SIRT3 was the primary goal of the current investigation. Virtual screening of ~ 800 compounds using molecular docking techniques yielded 8 active hits with favorable binding affinities and poses. Docking studies verified that the final eight compounds formed stable contacts with the catalytic domain of SIRT3. Those compounds have good pharmacokinetic/dynamic properties and gastrointestinal absorption. Based on excellent pharmacokinetic and pharmacodynamic properties, two compounds (MI-44 and MI-217) were subjected to MD simulation. Upon drug interaction, molecular dynamics simulations demonstrate mild alterations in the structure of proteins and stability. Binding free energy calculations revealed that compounds MI-44 (- 45.61 ± 0.064 kcal/mol) and MI-217 (- 41.65 ± 0.089 kcal/mol) showed the maximum energy, suggesting an intense preference for the SIRT3 catalytic site for attachment. The in-vitro MTT assay on breast cancer cell line (MDA-MB-231) and an apoptotic assay for these potential compounds (MI-44/MI-217) was also performed, with flow cytometry to determine the compound's ability to cause apoptosis in breast cancer cells. The percentage of apoptotic cells (including early and late apoptotic cells) increased from 1.94% in control to 79.37% for MI-44 and 85.37% for MI-217 at 15 µM. Apoptotic cell death was effectively induced by these two compounds in a flow cytometry assay indicating them as a good inhibitor of human SIRT3. Based on our findings, MI-44 and MI-217 merit additional investigation as possible breast cancer therapeutics.

Surface-Functionalized Magnetic Silica-Malachite Tricomposite (Fe-M-Si tricomposite): A Promising Adsorbent for the Removal of Cypermethrin.

This study assessed the efficacy of adsorption for eliminating the agricultural pesticide cypermethrin (CP) from wastewater using various adsorbents: silica, malachite, and magnetite. Magnetic nanocomposites (NCs) (with varying amounts of Fe3O4 0.1, 0.25, 0.5, 1.0, and 1.5 wt/wt %) were synthesized, including Fe3O4 nanoparticles (NPs), bicomposites, and tricomposites, calcined at 300 and 500 °C, and then tested for CP removal. The study was conducted in two phases, with the objective of initially assessing how effectively each individual NP performed and then evaluating how effectively the NCs performed when used for the adsorption of CP. Notably, the Fe3O4-malachite combination exhibited superior CP removal, with the 0.25-Fe-M NC achieving the highest adsorption at 635.4 mg/g. This success was attributed to the large surface area, magnetic properties of Fe3O4, and adsorption capabilities of malachite. The Brunauer-Emmett-Teller (BET) isotherm analysis indicated that the NCs had potential applications in adsorption and separation processes. The scanning electron microscopy and transmission electron microscopy revealed the spherical, irregular shaped morphology of the synthesized NPs and NCs. However, the X-ray diffraction (XRD) pattern of surface functionalized materials such as surface functionalized malachite [Cu2CO3(OH)2] with Fe3O4 and SiO2 may be complicated by the specific functionalization method used and the relative amounts and crystallographic orientations of each component. Therefore, careful interpretation and analysis of the XRD pattern, along with other techniques, are necessary for accurate identification and characterization of the functionalized material. The originality of this study lies in its comprehensive investigation of several adsorbents and NCs for CP removal at neutral pH. The innovation stems from the synergistic action of Fe3O4 and malachite, which results in improved CP removal due to their combined surface properties and magnetic characteristics. The application of magnetic NCs in adsorption and separation, as validated by BET isotherm analysis, highlights the potential breakthrough in addressing pesticide contamination.

Novel Natural Inhibitors for Glioblastoma by Targeting Epidermal Growth Factor Receptor and Phosphoinositide 3-kinase.

BACKGROUND/AIM: Glioblastoma is an extensively malignant neoplasm of the brain that predominantly impacts the human population. To address the challenge of glioblastoma, herein, we have searched for new drug-like candidates by extensive computational and biochemical investigations. METHOD: Approximately 950 compounds were virtually screened against the two most promising targets of glioblastoma, i.e., epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K). Based on highly negative docking scores, excellent binding capabilities and good pharmacokinetic properties, eight and seven compounds were selected for EGFR and PI3K, respectively. RESULTS: Among those hits, four natural products (SBEH-40, QUER, QTME-12, and HCFR) exerted dual inhibitory effects on EGFR and PI3K in our in-silico analysis; therefore, their capacity to suppress the cell proliferation was assessed in U87 cell line (type of glioma cell line). The compounds SBEH-40, QUER, andQTME-12 exhibited significant anti-proliferative capability with IC50 values of 11.97 ± 0.73 µM, 28.27 ± 1.52 µM, and 22.93 ± 1.63 µM respectively, while HCFR displayed weak inhibitory potency (IC50 = 74.97 ± 2.30 µM). CONCLUSION: This study has identified novel natural products that inhibit the progression of glioblastoma; however, further examinations of these molecules are required in animal and tissue models to better understand their downstream targeting mechanisms.

Discovery of Novel Natural Inhibitors Against SARS-CoV-2 Main Protease: A Rational Approach to Antiviral Therapeutics.

BACKGROUND/AIM: The global pandemic caused by the novel SARS-CoV-2 virus underscores the urgent need for therapeutic interventions. Targeting the virus's main protease (Mpro), crucial for viral replication, is a promising strategy. OBJECTIVE: The current study aims to discover novel inhibitors of Mpro. METHODS: The current study identified five natural compounds (myrrhanol B (C1), myrrhanone B (C2), catechin (C3), quercetin (C4), and feralolide (C5) with strong inhibitory potential against Mpro through virtual screening and computational methods, predicting their binding efficiencies and validated it using the in-vitro inhibition activity. The selected compound's toxicity was examined using the MTT assay on a human BJ cell line. RESULTS: Compound C1 exhibited the highest binding affinity, with a docking score of -9.82 kcal/mol and strong hydrogen bond interactions within Mpro's active site. A microscale molecular dynamics simulation confirmed the stability and tight fit of the compounds in the protein's active pocket, showing superior binding interactions. in vitro assays validated their inhibitory effects, with C1 having the most significant potency (IC50 = 2.85 µM). The non-toxic nature of these compounds in human BJ cell lines was also confirmed, advocating their safety profile. CONCLUSION: These findings highlight the effectiveness of combining computational and experimental approaches to identify potential lead compounds for SARS-CoV-2, with C1-C5 emerging as promising candidates for further drug development against this virus.

Preparation and characterization of sulphur and zinc oxide Co-doped graphitic carbon nitride for photo-assisted removal of Safranin-O dye.

Recently, there has been significant interest in photocatalytic reactions involving graphitic carbon nitride (g-C3N4) due to its sp2-hybridized carbon and nitrogen content and it is an ideal candidate for blending with other materials to enhance performance. Here, we have synthesized and analyzed both doped and undoped g-C3N4 nanoparticles. Specifically, we co-doped sulfur (S) into g-C3N4, integrated it with ZnO particles, and investigated the photocatalytic potential of these nanocomposites to remove Safranin-O dye. The initial step involved the preparation of pure g-C3N4 through calcination of urea. Subsequently, S-g-C3N4 was synthesized by calcining a mixture of urea and thiourea with a 3 : 1 ratio. Finally, the ZnO-S-g-C3N4 composite was synthesized using the liquid exfoliation technique, with distilled water serving as the exfoliating solvent. These samples were characterized by advanced techniques, including UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FTIR), X-ray Diffraction (XRD), energy dispersive X-ray (EDX) and scanning electron microscopy (SEM), to assess their crystallinity, morphology, optical properties, and phase purity. Subsequently, these nanocomposites were employed in catalytic and photocatalytic processes to remove the Safranin-O dye (SO). The results highlighted the formation of Z-scheme junction responsible for ZnO-S-g-C3N4's significant performance improvement. The comparison of results demonstrated that S-g-C3N4 and ZnO-S-g-C3N4 composites revealed an effective removal of Safranin-O dye in the presence of UV-light as compared to pure g-C3N4, as it was attributed to the phenomenon of improved separation of photogenerated charge carriers as a result of heterojunction formation between S-g-C3N4 and ZnO interfaces. In addition to improving photocatalytic performance, this study presents a facile route for producing ZnO-S-g-C3N4 composite with superior adsorption capabilities and selectivity.

Assessment of ubiquitin specific Peptidase-18 gene in peripheral blood of chronic hepatitis C patients treated with direct-acting antiviral drugs.

Hepatitis C virus (HCV) infection remains one of the leading causes of liver complications globally. Ubiquitin Specific Peptidase-18 (USP18) is a ubiquitin-specific protease that cleaves interferon-stimulated gene 15 (ISG15) from ISGylated protein complexes and is involved in regulating interferon responsiveness. To study the effect of direct-acting antivirals (DAAs) on the USP18 gene using qPCR, 132 participants were recruited and classified into different groups based on treatment duration. USP18 expression was raised compared to rapid virologic response (RVR) and early virologic response (EVR) groups with P = 0.0026 and P = 0.0016, respectively. USP18 was found to be 7.36 folds higher in naïve patients than those with RVR and sustained viral response (SVR). In RVR and SVR groups where patients had cleared HCV RNA after treatment with direct-acting antiviral agents (DAA) therapy, the expression of USP18 was found to be low, with a fold change of 1.3 and 1.4 folds, respectively. Expression of USP18 was significantly higher in the non-RVR group than in the RVR group. In the No EVR group, gene expression was significantly higher than in the EVR group. It is concluded that targeting HCV proteins using DAAs can cause USP18 expression to be normalized more effectively. Moreover, USP18 is a vital marker indicating treatment resistance and distinguishing responders from non-responders during DAA therapy.

Targeting papain-like protease by natural products as novel therapeutic potential SARS-CoV-2.

The highly infectious respiratory illness 'COVID-19' was caused by SARS-CoV-2 and is responsible for millions of deaths. SARS-single-stranded viral RNA genome encodes several structural and nonstructural proteins, including papain-like protease (PLpro), which is essential for viral replication and immune evasion and serve as a potential therapeutic target. Multiple computational techniques were used to search the natural compounds that may block the protease and deubiquitinase activities of PLpro. Five compounds showed strong interactions and binding energy (ranges between -8.18 to -8.69 Kcal/mol) in our in-silico studies. Interestingly, those molecules strongly bind in the PLpro active site and form a stable complex, as shown by microscale molecular dynamic simulations (MD). The dynamic movements indicate that PLpro acquires closed conformation by the attachment of these molecules, thereby changing its normal function. In the in-vitro evaluation, compound COMP4 showed the most potent inhibitory potential for PLpro (protease activity: 2.24 ± 0.17 µM and deubiquitinase activity: 1.43 ± 0.14 µM), followed by COMP1, 2, 3, and 5. Furthermore, the cytotoxic effect of COMP1-COMP5 on a human BJ cell line revealed that these compounds demonstrate negligible cytotoxicity at a dosage of 30 µM. The results suggest that these entities bear therapeutic efficacy for SARS-CoV-2 PLpro.