Preferential Solvation Study of Rosuvastatin in the {PEG400 (1) + Water (2)} Cosolvent Mixture and GastroPlus Software-Based In Vivo Predictions

Article claims that rosuvastatin (RST) is a poorly water-soluble drug responsible for limited in vivo dissolution and subsequently low oral systemic absorption (poor bioavailability). The results of inverse Kirkwood–Buff integrals showed the PS of RST by PEG400 as observed in all studied ratios of the binary mixture

Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase

Ten benzoxazole clubbed 2-pyrrolidinones (11–20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11–20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO2 derivative) and 20 (4-SO2NH2 derivative), with an IC50 value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC50 value above 50 µM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 Å) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively

Cardioprotective Effect of Tangeretin by Inhibiting PTEN/AKT/mTOR Axis in Experimental Sepsis-Induced Myocardial Dysfunction

Sepsis aggregates undesirable immune response causing depression of ventricular myocardium and diastolic dysfunction. This present study examined the effect of a plant-derived flavone tangeretin (TG) on autophagy and reduction in myocardial dysfunction. The sepsis was induced by cecum ligation and puncture (CLP) in male Sprague–Dawley rats. Abnormal changes were seen in the heart after the sepsis induction. These abnormalities were analyzed based on the cardiac markers, namely Cardiac myosin light chain-1 (cMLC1) and Cardiac troponin I (cTnl), echocardiography, and plasma parameters, like Lactate dehydrogenase (LDH) and Creatinine kinase (CK). Microanatomy of the heart was studied using hematoxylin and eosin stained histopathological samples of cardiac tissue. Western blot technique was used to detect the nature and extent of protein with the amount of a specific RNA (gene expression) in the cardiac homogenate. Oxidative damage was analyzed using redox marker, reduced glutathione. This study successfully showed that TG attenuated sepsis-induced myocardial dysfunction by inhibiting myocardial autophagy via silencing the Phosphatase and tensin homolog (PTEN) expression and acting on the AKT/mTOR pathway. The present findings supported that TG is a novel cardioprotective therapeutic target for sepsis induced myocardial dysfunction

Ameliorative Effect of Ethanolic Extract of <i>Moringa oleifera</i> Leaves in Combination with Curcumin against PTZ-Induced Kindled Epilepsy in Rats: In Vivo and In Silico

The ameliorative effect of ethanolic extract of M. oleifera (MOEE) leaves in combination with curcumin against seizures, cognitive impairment, and oxidative stress in the molecular docking of PTZ-induced kindled rats was performed to predict the potential phytochemical effects of MOEE and curcumin against epilepsy. The effect of pretreatment with leaves of M. oleifera ethanolic extracts (MOEE) (250 mg/kg and 500 mg/kg, orally), curcumin (200 mg/kg and 300 mg/kg, orally), valproic acid used as a standard (100 mg/kg), and the combined effect of MOEE (250 mg/kg) and curcumin (200 mg/kg) at a low dose on Pentylenetetrazole was used for (PTZ)-induced kindling For the development of kindling, individual Wistar rats (male) were injected with pentyletetrazole (40 mg/kg, i.p.) on every alternate day. Molecular docking was performed by the Auto Dock 4.2 tool to merge the ligand orientations in the binding cavity. From the RCSB website, the crystal structure of human glutathione reductase (PDB ID: 3DK9) was obtained. Curcumin and M. oleifera ethanolic extracts (MOEE) showed dose-dependent effects. The combined effects of MOEE and curcumin leaves significantly improved the seizure score and decreased the number of myoclonic jerks compared with a standard dose of valproic acid. PTZ kindling induced significant oxidative stress and cognitive impairment, which was reversed by pretreatment with MOEE and curcumin. Glutathione reductase (GR) is an enzyme that plays a key role in the cellular control of reactive oxygen species (ROS). Therefore, activating GR can uplift antioxidant properties, which leads to the inhibition of ROS-induced cell death in the brain. The combination of the ethanolic extract of M. oleifera (MOEE) leaves and curcumin has shown better results than any other combination for antiepileptic effects by virtue of antioxidant effects. As per the docking study, chlorogenic acid and quercetin treated with acombination of curcumin have much more potential

Design, Synthesis, ADME, and Anticancer Studies of Newer <i>N</i>‑Aryl-5-(3,4,5-Trifluorophenyl)-1,3,4-Oxadiazol-2-Amines: An Insight into Experimental and Theoretical Investigations

In continuance of our investigation into the anticancer activity of oxadiazoles, we report here the preparation of 10 new 1,3,4-oxadiazole analogues using the scaffold hopping technique. We have prepared the oxadiazoles having a common pharmacophoric structure (oxadiazole linked aryl nucleus) as seen in the reported anticancer agents IMC-038525 (tubulin inhibitor), IMC-094332 (tubulin inhibitor), and FATB (isosteric replacement of the S of thiadiazole with the O of oxadiazole). All of the oxadiazole analogues were predicted for their absorption, distribution, metabolism, and excretion (ADME) profiles and toxicity studies. All of the compounds were found to follow Lipinski’s rule of 5 with a safe toxicity profile (Class IV compound) against immunotoxicity, mutagenicity, and toxicity. All of the compounds were synthesized and characterized using spectral data, followed by their anticancer activity tested in a single-dose assay at 10 μM as reported by the National Cancer Institute (NCI US) Protocol against nearly 59 cancer cell lines obtained from nine panels, including non-small-cell lung, ovarian, breast, central nervous system (CNS), colon, leukemia, prostate, and cancer melanoma. N-(2,4-Dimethylphenyl)-5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-amine (6h) displayed significant anticancer activity against SNB-19, OVCAR-8, and NCI-H40 with percent growth inhibitions (PGIs) of 86.61, 85.26, and 75.99 and moderate anticancer activity against HOP-92, SNB-75, ACHN, NCI/ADR-RES, 786-O, A549/ATCC, HCT-116, MDA-MB-231, and SF-295 with PGIs of 67.55, 65.46, 59.09, 59.02, 57.88, 56.88, 56.53, 56.4, and 51.88, respectively. The compound 6h also registered better anticancer activity than Imatinib against CNS, ovarian, renal, breast, prostate, and melanoma cancers with average PGIs of 56.18, 40.41, 36.36, 27.61, 22.61, and 10.33, respectively. Molecular docking against tubulin, one of the appealing cancer targets, demonstrated an efficient binding within the binding site of combretastatin A4. The ligand 6h (docking score = −8.144 kcal/mol) interacted π-cationically with the residue Lys352 (with the oxadiazole ring). Furthermore, molecular dynamic (MD) simulation studies in complex with the tubulin-combretastatin A4 protein and ligand 6h were performed to examine the dynamic stability and conformational behavior

Kaempferol: Paving the path for advanced treatments in aging-related diseases

Aging-related diseases (ARDs) are a major global health concern, and the development of effective therapies is urgently needed. Kaempferol, a flavonoid found in several plants, has emerged as a promising candidate for ameliorating ARDs. This comprehensive review examines Kaempferol's chemical properties, safety profile, and pharmacokinetics, and highlights its potential therapeutic utility against ARDs. Kaempferol's therapeutic potential is underpinned by its distinctive chemical structure, which confers antioxidative and anti-inflammatory properties. Kaempferol counteracts reactive oxygen species (ROS) and modulates crucial cellular pathways, thereby combating oxidative stress and inflammation, hallmarks of ARDs. Kaempferol's low toxicity and wide safety margins, as demonstrated by preclinical and clinical studies, further substantiate its therapeutic potential. Compelling evidence supports Kaempferol's substantial potential in addressing ARDs through several mechanisms, notably anti-inflammatory, antioxidant, and anti-apoptotic actions. Kaempferol exhibits a versatile neuroprotective effect by modulating various proinflammatory signaling pathways, including NF-kB, p38MAPK, AKT, and the β-catenin cascade. Additionally, it hinders the formation and aggregation of beta-amyloid protein and regulates brain-derived neurotrophic factors. In terms of its anticancer potential, kaempferol acts through diverse pathways, inducing apoptosis, arresting the cell cycle at the G2/M phase, suppressing epithelial-mesenchymal transition (EMT)-related markers, and affecting the phosphoinositide 3-kinase/protein kinase B signaling pathways. Subsequent studies should focus on refining dosage regimens, exploring innovative delivery systems, and conducting comprehensive clinical trials to translate these findings into effective therapeutic applications