Synthesis, molecular docking, and dynamic simulation targeting main protease (Mpro) of new, Thiazole clubbed pyridine scaffolds as potential COVID-19 inhibitors

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N′-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = −8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19

Cytotoxic activity of Thymus capitatus collected from Hail region in Saudi Arabia with mechanistic study via induction of caspase-dependent apoptosis and S-phase arrest

Thymus capitatus is a plant grows in Mediterranean area and some Arab countries such as Saudi Arabia. It possesses numerous medicinal values. Its common name is Zaatar and it belongs to family Lamiaceae Thymus capitatus leaves and stem were collected from Hail region, Saudi Arabia. Then both leaves and stem were extracted with ethanol. This study was performed to evaluate cytotoxic activity of Thymus capitatus leaves and stem ethanolic extract in details. Doxorubicin was used as a standard and the relevant half maximal inhibitory concentration (IC50) values were computed for each cell line by 3-(4,5- diemthylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. In addition, further mechanistic study was carried out by using Apoptosis assay to explore cytotoxic activity of plant extract. Both leaves and stems extracts were screened against HepG2, A-549, HCT-116 and   MCF-7 cancer cell lines. It was found that leaves’ extract shows high and moderate cytotoxic activity against both A-549 and HepG2 cancer cell lines, respectively (with IC50 = 13.6 and 21.5 μg/ml, respectively), while stem’s extract exerted moderate cytotoxic activity against A-549 cancer cell lines (with IC50 = 21.38 μg/ml).  Further mechanistic study was carried out on A-549 cells by using apoptosis assay. It showed that leaves’ extract resulted in arrest of S-phase and caused apoptosis through activation of caspase-3, p53 and Bax, in addition to down regulation of Bcl-2

GC–MS analysis, molecular docking, and pharmacokinetic studies of Multidentia crassa extracts’ compounds for analgesic and anti-inflammatory activities in dentistry

Abstract Plant extracts have been useful for oral health or dentistry. However, only a few evidence-based justifications exist. This study evaluated Multidentia crassa (Hiern) Bridson & Verdc, one of the oral health-used plants in Malawi. Gas chromatography-mass spectrometry (GC-MS) and Fourier transform infrared (FT-IR) identified the extracts’ compounds. The pharmacokinetics of the identified compounds were studied using pkCSM and SwissADME, and molecular docking studies were used to identify potential drug candidates for oral health by predicting the binding affinity of the compounds to cyclooxygenases, interleukin-1 beta receptors, odontoblast cold sensor proteins, and purinergic receptor P2X3. FT-IR analysis showed characteristic peaks of phenols, carboxylic acids, alkenes, alkyl halides, amines, esters, ethers, aromatics, and lipids. GC–MS results showed the presence of 58 bioactive phytocompounds, some of which have various pharmacological activities relevant to oral health. Molecular docking further validated stigmastan-3,5-diene’s potency for analgesic and anti-inflammatory purposes. Based on a literature review, this is the first report on the bioactive compounds of M. crassa extracts showing analgesic and anti-inflammatory effects. This study's results can lead to new herbal and conventional medicines. Therefore, we recommend in vivo and in vitro studies to elucidate the pharmacological effects of the plant extracts

In Vivo and In Silico Analgesic Activity of Ficus populifolia Extract Containing 2-O-β-D-(3′,4′,6′-Tri-acetyl)-glucopyranosyl-3-methyl Pentanoic Acid

Natural product-based structural templates have immensely shaped small molecule drug discovery, and new biogenic natural products have randomly provided the leads and molecular targets in anti-analgesic activity spheres. Pain relief achieved through opiates and non-steroidal anti-inflammatory drugs (NSAIDs) has been under constant scrutiny owing to their tolerance, dependency, and other organs toxicities and tissue damage, including harm to the gastrointestinal tract (GIT) and renal tissues. A new, 3′,4′,6′-triacetylated-glucoside, 2-O-β-D-(3′,4′,6′-tri-acetyl)-glucopyranosyl-3-methyl pentanoic acid was obtained from Ficus populifolia, and characterized through a detailed NMR spectroscopic analysis, i.e., 1H-NMR, 13C-DEPT-135, and the 2D nuclear magnetic resonance (NMR) correlations. The product was in silico investigated for its analgesic prowess, COX-2 binding feasibility and scores, drug likeliness, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, possible biosystem’s toxicity using the Discovery Studio®, and other molecular studies computational software programs. The glycosidic product showed strong potential as an analgesic agent. However, an in vivo evaluation, though at strong levels of pain-relieving action, was estimated on the compound’s extract owing to the quantity and yield issues of the glycosidic product. Nonetheless, the F. populifolia extract showed the analgesic potency in eight-week-old male mice on day seven of the administration of the extract’s dose in acetic acid-induced writhing and hot-plate methods. Acetic acid-induced abdominal writhing for all the treated groups decreased significantly (p < 0.0001), as compared to the control group (n = 6) by 62.9%, 67.9%, and 70.9% of a dose of 100 mg/kg (n = 6), 200 mg/kg (n = 6), and 400 mg/kg (n = 6), respectively. Similarly, using the analgesia meter, the reaction time to pain sensation increased significantly (p < 0.0001), as compared to the control (n = 6). The findings indicated peripheral and central-nervous-system-mediated analgesic action of the product obtained from the corresponding extract

In Vivo and In Silico Analgesic Activity of <i>Ficus populifolia</i> Extract Containing 2-O-β-D-(3′,4′,6′-Tri-acetyl)-glucopyranosyl-3-methyl Pentanoic Acid

Natural product-based structural templates have immensely shaped small molecule drug discovery, and new biogenic natural products have randomly provided the leads and molecular targets in anti-analgesic activity spheres. Pain relief achieved through opiates and non-steroidal anti-inflammatory drugs (NSAIDs) has been under constant scrutiny owing to their tolerance, dependency, and other organs toxicities and tissue damage, including harm to the gastrointestinal tract (GIT) and renal tissues. A new, 3′,4′,6′-triacetylated-glucoside, 2-O-β-D-(3′,4′,6′-tri-acetyl)-glucopyranosyl-3-methyl pentanoic acid was obtained from Ficus populifolia, and characterized through a detailed NMR spectroscopic analysis, i.e., 1H-NMR, 13C-DEPT-135, and the 2D nuclear magnetic resonance (NMR) correlations. The product was in silico investigated for its analgesic prowess, COX-2 binding feasibility and scores, drug likeliness, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, possible biosystem’s toxicity using the Discovery Studio®, and other molecular studies computational software programs. The glycosidic product showed strong potential as an analgesic agent. However, an in vivo evaluation, though at strong levels of pain-relieving action, was estimated on the compound’s extract owing to the quantity and yield issues of the glycosidic product. Nonetheless, the F. populifolia extract showed the analgesic potency in eight-week-old male mice on day seven of the administration of the extract’s dose in acetic acid-induced writhing and hot-plate methods. Acetic acid-induced abdominal writhing for all the treated groups decreased significantly (p p < 0.0001), as compared to the control (n = 6). The findings indicated peripheral and central-nervous-system-mediated analgesic action of the product obtained from the corresponding extract

A generalization of Jeffrey-Hamel problem to Reiner-Rivlin model for energy and thermodynamic analysis using Keller-Box computational framework

This study addresses the heat transport and irreversible mechanisms associated with energy and frictional losses in the Jeffery-Hamel flow of a non-Newtonian fluid adapting the Reiner-Rivlin model. The Reiner-Rivlin model is frequently used to tackle the impact of yield-stresses among the multiple rheological models suggested for constructing the flow of yield-stresses materials. The non-creeping flow between convergent and divergent plates (Jeffrey-Hamel flow), the viscoelastic characteristics of incompressible Reiner-Rivlin liquid are examined by adapting the Navier-Stokes flow. The flow of a Reiner-Rivlin fluid is caused by pressure differential at the inlet. The second law of thermodynamics ultimately provide entropy manifestation. Using a comprehensive Keller-Box approach, self-similar numerical solutions for the velocity and associated fields are provided. The distribution of velocities for fluid-specific characteristics reveals an impedance formed by interaction between wall and diverging flow orientations. Viscous dissipation has a notable impact on the irreversible process and subsequently enhance the transmission of heat. Irrespective of the conduit structure, the Eckert number raises both the centerline and wall temperatures. The wall temperature gradient show a dominant trend for diverging channel. Higher Brinkman number, particularly in the context of the Reiner-Rivlin fluid, render the effect of viscous dissipation on the development of entropy apparent

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N&prime;-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = &minus;8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N′-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = −8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19

Assessment of solid-dosage drug nanonization by theoretical advanced models: Modeling of solubility variations using hybrid machine learning models

Production of solid-dosage drug nanoparticles was assessed by theoretical models to investigate the possibility of drug treatment via supercritical green processing. Nanonization can enhance drug solubility and consequently its bioavailability which is of great importance for pharmaceutical industry. This research presents a comparative study of three different regression models including Gaussian process regression, k-nearest neighbors, and multi-layer perceptron for predicting solvent density and solubility of Hyoscine drug. The models optimized using political optimizer (PO) algorithm. The results showed that all three optimized methods were able to predict density and solubility with high accuracy. PO-GPR achieved the highest R2 score for solubility (0.9984) and same for density (0.9999). The PO-MLP model achieved the high R2 score for density (0.9997) and the second-highest score for solubility (0.9945). PO-KNN also showed good performance for density (R2 = 0.9557) and solubility (R2 = 0.9783) but was outperformed by the other two models. In terms of RMSE and AARD%, PO-GPR and PO-MLP achieved lower error rates compared to PO-KNN. Overall, the results suggest that PO-GPR and PO-MLP are promising methods for predicting density and solubility of values. The models were useful for the application of drug nanonization and can be used to optimize the process

Phytochemical and biological activity profiles of Thymbra linearifolia: An exclusively native species of Libyan Green mountains

Thymbra linearifolia, a Green Mountain endemic Libyan plant species belonging to the family Lamiaceae, was investigated as the plant's first documented phytochemical and biological evaluation report. The plant is used for bronchitis, cough, asthma, and gastrointestinal ailments, including dyspepsia, colic pain, and diarrhea. The phenolic and flavonoid contents of T. linearifolia were analyzed qualitatively and quantitatively by LC-MS analysis and spectrophotometric assays. These analyses revealed the presence of 60.67 mg/g of GAE (Gallic Acid Equivalents) and 26.79 mg/g of RE (Rutin Equivalents) of the phenolics and flavonoids, respectively, in the aerial parts of the plants’ ethanolic extract. Cyanidin-3-O-rutinoside (2.26 %), pelargonidin-3-O-rutinoside (2.36 %), gallocatechin (2.94 %), taxifolin (1.22 %), kaempferol-3-O-rutinoside (0.81 %), quercetin-3-O-retinosie (1.20 %), luteolin (0.99 %), apigenin (2.0 %), dimethoxy luteolin (2.97 %), and pinobanksin-3-O-acetate (2.56 %) were detected to be the major flavonoids, whereas the syringic acid hexoside (1.38 %), and rosmarinic acid (2.54 %) were among the most abundant phenolic acids in the plant’s extract. The DPPH scavenging activity was measured at an IC50 value of 34.48 μg/mL. In addition, potential reducing, metal chelating, and free radical scavenging potentials were exhibited in the in vitro assays, i.e., ABST, ORAC, FRAP, and MC. The remarkable antioxidant activity of the plant was attributed to its phenolic and flavonoid contents. The plant extract had strong cytotoxic effects on three types of cancer cell lines, i.e., MCF-7, HepG2, and Panc-1, with IC50 values of 24.023, 22.94, and 33.30 μg/mL, respectively. Furthermore, the plant extract also exhibited cytotoxic effects greater than the standard anticancer drug, doxorubicin, against all the tested cell lines. The in-silico binding studies also demonstrated that the phytochemical constituents of T. linearifolia have a high binding affinity against the epidermal growth factor receptor (EGFR) protein, which supported the anticancer potentials of the plant. The antimicrobial assay conducted with the well-diffusion method revealed the moderate effects of the plant’s extract against Bacillus subtilis, Staphylococcus aureus, Saccharomyces cerevisiae, and Candida albicans. However, weak antimicrobial effects were recorded against the Gram-negative bacteria, Escherichia coli, and Salmonella typhimurium. These findings corroborated the immense health benefits of the plant, and substantiated the medicinal value claims of the plant, which is currently under use in different forms as part of the locals’ folk-medicinal chest