In vitro and in silico studies of fluorinated 2,3-disubstituted thiazolidinone-pyrazoles as potential α-amylase inhibitors and antioxidant agents.

As part of our effort to identify potent α-amylase inhibitors, in the present study, a novel series of fluorinated thiazolidinone-pyrazole hybrid molecules were prepared by the condensation of 3-(aryl/benzyloxyaryl)-pyrazole-4-carbaldehydes with fluorinated 2,3-disubstituted thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and liquid chromatography-mass spectrometry data. All the compounds were screened for their α-amylase inhibitory and free radical scavenging activities by DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS methods. Among the tested compounds, compound 8g emerged as a promising α-amylase inhibitor with IC50 = 0.76 ± 1.23 µM, and it was found to be more potent than the standard drug acarbose (IC50 = 0.86 ± 0.81 µM). Compounds 8b and 8g showed strong free radical scavenging activity compared to the standard butylated hydroxyl anisole. The kinetic study of compound 8g revealed the reversible, classical competitive inhibition mode on the α-amylase enzyme. Molecular docking and dynamic simulations studies were performed for the most potent compound 8g, which displayed remarkable hydrogen bonding with the α-amylase protein (PDB ID: 1DHK).

New insights on the phytochemical intervention for the treatment of neuropsychiatric disorders using the leaves of Michelia champaca: an in vivo and in silico approach.

CONTEXT: Michelia champaca L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties. OBJECTIVE: The ethanol extract of Michelia champaca leaves (EEMC) was evaluated on depression and anxiety using in vivo and in silico studies. MATERIALS AND METHODS: Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The in silico studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis. RESULTS: Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. In silico studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively. CONCLUSIONS: EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.

Investigation of antihyperglycaemic activity of banana (Musa sp. var. Nanjangud rasa bale) pseudostem in normal and diabetic rats.

BACKGROUND: Postprandial hyperglycaemia in diabetes could be ameliorated by inhibiting intestinal α-glucosidases, responsible for starch hydrolysis and its absorption. Different parts of banana have been in use in conventional medicinal formulations since ancient times. Its role as an antihyperglycaemic agent has also been studied. This study was aimed at explaining the mechanism of hypoglycaemic effect by ethanol extract of banana pseudostem (EE). Additionally, studies on the active components involved in the effect have also been attempted. RESULTS: EE significantly inhibited mammalian intestinal α-glucosidases and yeast α-glucosidase (IC50 , 8.11 ± 0.10 µg mL(-1) ). The kinetic studies showed that EE inhibited sucrase, maltase and and p-nitrophenyl-α-d-glucopyranoside hydrolysis by mixed-type inhibition. Further, in vivo studies identified that the oral administration (100-200 mg kg(-1) body weight) of EE significantly suppressed the maltose/glucose-induced postprandial plasma glucose elevation and wielded an antihyperglycaemic effect in normal and alloxan-induced diabetic rats. GC-MS analysis of EE revealed high levels of ß-sitosterol (29.62%), stigmasterol (21.91%), campesterol (10.85%) and other compounds. CONCLUSION: These findings suggest that EE might exert an anti-diabetic effect by inhibition of α-glucosidases from the intestine, in turn suppressing the carbohydrate absorption into the bloodstream. Hence the results extend a foundation to the future prospects of the food-derived enzyme inhibitors in treatment of diabetes.

Computational approaches to define poncirin from Magnolia champaka leaves as a novel multi-target inhibitor of SARS-CoV-2.

Phytochemical-based drug discovery against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been the focus of the current scenario. In this context, we aimed to perform the phytochemical profiling of Magnolia champaka, an evergreen tree from the Magnoliaceae family, in order to perform a virtual screening of its phytoconstituents against different biological targets of SARS-CoV-2. The phytochemicals identified from the ethanol extract of M. champaka leaves using liquid chromatography-mass spectroscopy (LC-MS) technique were screened against SARS-CoV-2 spike glycoprotein (PDB ID: 6M0J), main protease/Mpro (PDB ID: 6LU7), and papain-like protease/PLpro (PDB ID: 7CMD) through computational tools. The experimentation design included molecular docking simulation, molecular dynamics simulation, and binding free energy calculations. Through molecular docking simulation, we identified poncirin as a common potential inhibitor of all the above-mentioned target proteins. In addition, molecular dynamics simulations, binding free energy calculations, and PCA analysis also supported the outcomes of the virtual screening. By the virtue of all the in silico results obtained, poncirin could be taken for in vitro and in vivo studies in near future.Communicated by Ramaswamy H. Sarma.

Molecular insights into the in silico discovery of corilagin from Terminalia chebula as a potential dual inhibitor of SARS-CoV-2 structural proteins.

The spike (S) glycoprotein and nucleocapsid (N) proteins are the crucial pathogenic proteins of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus during its interaction with the host. Even FDA-approved drugs like dexamethasone and grazoprevir are not able to curb the viral progression inside the host and are reported with adverse effects on body metabolism. In this context, we aim to report corilagin a novel, potential dual inhibitor of S and N proteins from Terminalia chebula. The bioactive compounds of T. chebula were subjected to a series of computational investigations including molecular docking simulations, molecular dynamics (MD) simulations, binding free energy calculations, and PASS pharmacological analysis. The results obtained from these studies revealed that corilagin was highly interactive with the S (-8.9 kcal/mol) and N (-9.2 kcal/mol) proteins, thereby showing dual inhibition activity. It was also found to be stable enough to induce biological activity inside the inhibitor binding pocket of the target enzymes throughout the dynamics simulation run for 100 ns. This is also confirmed by the changes in the protein conformations, evaluated using free energy landscapes. Outcomes from this investigation identify corilagin as the lead potential dual inhibitor of S and N proteins of SARS-CoV-2, which could be taken for biological studies in near future.Communicated by Ramaswamy H. Sarma.

Azadirachta indica A. Juss (neem) against diabetes mellitus: a critical review on its phytochemistry, pharmacology, and toxicology.

OBJECTIVE: We aim to provide a critical review focused on the various pharmacological activities of Azadirachta indica A. Juss related to diabetes management. We also emphasise on phytochemistry and toxicology of A. indica, which could provide a comprehensive approach for plant-based drug development in future. KEY FINDINGS: From 2784 identified studies, only 83 were considered after double screening based on the inclusion criteria. Further, 63 pharmacological investigations were considered for review. Resultant studies deliberated on using different extracts and phytochemicals of A. indica on blood glucose level, lipid profile, oxidative stress, carbohydrate digestion enzymes, diabetic complications, glucose tolerance, and uptake of glucose. SUMMARY: In the end, one can know the efficacy of A. indica as a potent antidiabetic herbal medicine. However, based on gaps in research, recommendations have been provided to evaluate A. indica. in a systematic manner to develop plant-based drugs, nutraceuticals, and to evaluate their clinical efficiency and safety against diabetes mellitus.

2-methoxy-4-(((5-nitropyridin-2-yl)imino)methyl)phenol Schiff base ligand and its Cu(II) and Zn(II) complexes: synthesis, characterization and biological investigations.

In this current work we have prepared a Schiff base ligand, (HL) derived from 5- nitropyridine-2-amine with 4-hydroxy-3-methoxybenzaldehyde and its Cu(II), and Zn(II) in 2:1 stoichiometric ratio (2HL:M). The formation of the ligand and the metal complexes were evaluated by means of MS, FT-IR, UV-Visible, 1H-NMR, 13C-NMR and thermogravimetric methods. The free radical scavenging activity of compounds was evaluated through a sequence of in vitro assays viz., DPPH, ABTS and Superoxide where BHA was used as a positive controller. In vitro α-glucosidase inhibitory activities showed that complexes had considerable inhibitory potential when compared to the ligand.

Evaluation of flavonoids from banana pseudostem and flower (quercetin and catechin) as potent inhibitors of α-glucosidase: An in silico perspective.

The amelioration of postprandial hyperglycemia in diabetic conditions could be accomplished by the inhibition of α-glucosidases, a set of intestinal carbohydrate digestive enzymes responsible for starch hydrolysis and its absorption. The ethnopharmacological profile of banana depicts the usage of different plant parts in conventional medicinal formulations. The antidiabetic studies of the plant have demonstrated their ability to inhibit α-glucosidase. Besides, our research group has reported the α-glucosidase inhibitory potential of the banana pseudostem and flower extracts in previous studies. In this study, we deliberate on the specific phytoconstituents of banana pseudostem and flower to evaluate their antidiabetic effects through an in silico perspective for the α-glucosidase inhibition. In this context, several phytoconstituents of banana pseudostem and flower identified through GC-MS analysis were retrieved from chemical databases. These phytochemicals were virtually screened through the molecular docking simulation process, from which only two flavonoids (catechin and quercetin) were selected based on their binding affinity and extent of interaction with the α-glucosidase target protein. The lower binding affinities of catechin and quercetin in comparison with that of acarbose as a control proved their binding efficiency with the target protein. In addition, acarbose showed subservient molecular interaction, forming an unfavourable acceptor-acceptor bond. The molecular dynamics simulations also depicted the effective binding and stability of the complexes formed with catechin and quercetin, in comparison with that of acarbose. Further, PASS analysis, druglikeliness, and pharmacokinetic assessments showed that both catechin and quercetin edge over acarbose in terms of drug-score and pharmacokinetic properties. With the positive results obtained from contemporary strategies, the two flavonoids from banana pseudostem and flower might be established as a considerable phototherapeutic approach to inhibit α-glucosidase. Communicated by Ramaswamy H. Sarma.

In silico identification of novel benzophenone-coumarin derivatives as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors.

In this study, we propose our novel benzophenone-coumarin derivatives (BCDs) as potent inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus, one of the key targets that are involved in the viral genome replication. We aim to evaluate the in silico antiviral potential of BCDs against this protein target, which involves molecular docking simulations, druglikeliness and pharmacokinetic evaluations, PASS analysis, molecular dynamics simulations, and computing binding free energy. Out of all the BCDs screened through these parameters, BCD-8 was found to be the most efficient and potent inhibitor of SARS-CoV-2 RdRp. During molecular docking simulation, BCD-8 showed an extensive molecular interaction in comparison with that of the standard control used, remdesivir. The druglikeliness and pharmacokinetic analyses also proved the efficiency of BCD-8 as an effective drug without adverse effects. Further, pharmacological potential analysis through PASS depicted the antiviral property of BCD-8. With these findings, we performed molecular dynamics simulations, where BCD-8 edged out remdesivir with its exemplary stable interaction with SARS-CoV-2 RdRp. Furthermore, binding free energy of both BCD-8 and remdesivir was calculated, where BCD-8 showed a lower binding energy and standard deviations in comparison with that of remdesivir. Moreover, being a non-nucleoside analogue, BCD-8 can be used effectively against SARS-CoV-2, whereas nucleoside analogues like remdesivir may become non-functional or less functional due to exonuclease activity of nsp14 of the virus. Therefore, we propose BCD-8 as a SARS-CoV-2 RdRp inhibitor, showing higher predicted efficiency than remdesivir in all the in silico experiments conducted.Communicated by Ramaswamy H. Sarma.

A systematic review on ethnopharmacology, phytochemistry and pharmacological aspects of Thymus vulgaris Linn.

Thymus vulgaris Linn. is a medicinal and culinary herb from the Southern European region known for its anti-infective, cardioprotective, gastroprotective, anti-inflammatory, and immunomodulatory activities since the Egyptian era. The reported pharmacological activities of T. vulgaris L. include antibacterial, antioxidant, anti-inflammatory, antiviral, and anti-cancerous activities. In this review, a comprehensive approach is put forth to scrutinize and report the available data on phytochemistry, ethnopharmacology, pharmacology, and toxicology of the plant. The different extracts and essential oil obtained from the plant have been assessed and reported to treat ailments like microbial infections, inflammation, non-communicable diseases like cancer, and sexually transmitted diseases like HIV-1 and Herpes. The literature review has also indicated the use of volatile oils, phenolic acids, terpenoids, flavonoids, saponins, steroids, tannins, alkaloids, and polysaccharides in pharmacotherapy. Applications of these compounds including antidiabetic, anti-Alzheimer's, cardio, neuro and hepatoprotective, anti-osteoporosis, sedative, immunomodulatory, antioxidant, anti-tyrosinase, antispasmodic, antinociceptive, gastroprotective, anticonvulsant, antihypertensive, antidepressant, anti-amnesia, and anti-helminthic activities have been mentioned. Further, based on research gaps, recommendations have been provided to evaluate T. vulgaris L. systematically to develop plant-based drugs, nutraceuticals, and to evaluate their clinical efficiency and safety.

Azadirachta indica A. Juss (neem) as a contraceptive: An evidence-based review on its pharmacological efficiency.

BACKGROUND: Azadirachta indica A. Juss. is an Indian medicinal plant with innumerable pharmacological properties. Studies have proven that the phytochemicals from neem possess remarkable contraceptive abilities with limited knowledge on its mechanism of action. PURPOSE: The present review aims to summarize the efficiency of A. indica treatment as a contraceptive. METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used. Published scientific articles on antifertility, antispermatogenic, antiovulation, hormone altering, contraceptive, and abortifacient activities of A. indica were collected from reputed Journals from 1980 to 2020 using electronic databases. Specific keywords search was completed to collect numerous articles with unique experiment design and significant results. This was followed by the selection of the requisite articles based on the criteria designed by the authors. Data extraction was based on the common research elements included in the articles. RESULTS: A total of 27 studies were considered for reviewing, which included key pharmacological investigations. In the beginning, authors evaluated a number of publications on the contraceptive properties of A. indica, in which it was revealed that most of the publications were made between 2005 and 2009. All the collected articles were categorised and reviewed as antifertility, antispermatogenic, antiovulation, hormone altering, contraceptive, and abortifacient. Authors also assessed studies based on the plant parts used for pharmacological evaluations including leaves, seeds, stem-bark, and flowers. The article was primarily divided into different sections based on the previous works of authors on phytochemistry and pharmacological review articles. CONCLUSION: Although A. indica is not reported with the complete alleviation of reproductive system in both male and female animal models, studies have proven its efficacy as a contraceptive. Extracts and phytochemicals from neem neither reduced the libido nor retarded the growth of secondary sexual characters, thus indicating only a temporary and reversible contraceptive activity. However, there is a dearth for clinical studies to prove the efficacy of A. indica as a herbal contraceptive.

Design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein from Staphylococcus aureus.

It is of interest to document the design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein (PDB ID: 3VOB) from Staphylococcus aureus for antimicrobial applications. We report the quantitative structure function data in this context.

Toxicopathological studies on the effects of T-2 mycotoxin and their interaction in juvenile goats.

Food and feeds contaminated with mycotoxins have been a threat to the rearing industry by causing some of the most fatal toxic reactions not only in the farm animals but also in humans who consume them. Toxicity to juvenile goats was induced by feed contamination with T-2 toxin (at 10 and 20 ppm dosage; group I and II, respectively). The toxicity impact was assessed on days 15 and 30 post treatment with respect to growth performance, oxidative stress, apoptotic studies and detailed pathomorphology. The study revealed that apart from the obvious clinical toxicosis (weakness, lethargy, and retardation in growth), the toxin fed groups also exhibited significant haematological (reduced hemoglobin, total leukocyte and thrombocyte counts) and biochemical changes (increased levels of oxidative stress markers with concomitant decrease in levels of serum and tissue catalase and superoxide dismutase). The pathomorphological and histological alterations suggested that the liver and intestine were the most affected organs. Ultra-structurally, varying degrees of degeneration, cytoplasmic vacuolations and pleomorphic mitochondria were observed in the hepatocytes and the enterocytes of the intestine. Kidney also revealed extensive degeneration of the cytoplasmic organelles with similar condensation of the heterochromatin whereas the neuronal degeneration was characterized by circular, whirling structures. In addition, the central vein and portal triad of the hepatocytes, cryptic epithelial cells of the intestine, MLNs in the lymphoid follicles, PCT and DCT of the nephronal tissues and the white pulp of the spleen exhibited extensive apoptosis. In this study, it was also observed that the expression of HSPs, pro-apoptotic proteins and pro-inflammatory cytokines were significantly upregulated in response to the toxin treatment. These results suggest that the pathogenesis of T-2 toxicosis in goats employs oxidative, apoptotic and inflammatory mechanisms.

Investigation of Antihyperglycaemic Activity of Banana (Musa sp. Var. Nanjangud rasa bale) Flower in Normal and Diabetic Rats.

BACKGROUND: The vital enzymes of starch digestion and absorption are intestinal α-glucosidases and their inhibition improves postprandial hyperglycaemia, constituting an effective mode of therapy in diabetes. OBJECTIVES: The present study was designed to assess the inhibitory potential of ethanol extract of banana flower (EF) on mammalian α-glucosidases and its pharmacological effects on postprandial hyperglycaemia in normal and alloxan-induced diabetic rats. MATERIALS AND METHODS: EF was evaluated for its inhibitory potential and mode of inhibition on mammalian α-glucosidases. Further, the role of EF and its constituents Umbelliferone (C1) and Lupeol (C2) on glucose uptake using isolated rat hemi-diaphragm and insulinotropic activity using RINm5F (rat insulinoma) cell lines were determined. The phytocomponents in EF were also evaluated using GC-MS. RESULTS: EF illustrated a dose-dependent inhibition for rat intestinal sucrase, maltase and p-nitrophenyl-α-D-glucopyranoside (pNPG) hydrolysis (IC50 values: 18.76±0.22, 25.54±0.10 and 76.42±1.12 µg/ml, respectively) and the mode of inhibition was non-competitive with low Ki values. Oral administration (100-200 mg/kg b.wt.) of EF significantly improved the maltose/glucose-induced postprandial hyperglycaemia in normal and alloxan-induced diabetic rats. EF, C1 and C2 exhibited stimulation of glucose uptake and a dose-dependent glucose-induced insulin secretion at both 4.5 and 16.7 mM glucose concentrations. Further, GC-MS analysis revealed significant levels of steroids (25.61%), diazoprogesterone (21.31%), sesquiterpene (11.78%) and other phytocomponents. CONCLUSION: EF inhibited α-glucosidases besides promoting glucose uptake and insulin secretion, resulting in antihyperglycaemic effect determining EF as a potent anti-diabetic agent.Abbreviations used: mg/dl: milligramsper deciliter, mM: millimolar, b.wt.: body weight.

Assessment of Nutritional Quality and Global Antioxidant Response of Banana (Musa sp. CV. Nanjangud Rasa Bale) Pseudostem and Flower.

BACKGROUND: The assessment of the nutritional composition and phytochemical screening of banana pseudostem (PB) and flower (FB) advocate this nonconventional food source for routine consumption, considering its various health benefits. OBJECTIVES: The aim is to assess the proximate nutrient composition, fatty acids, minerals, amino acid profile, and global antioxidant response (GAR) of PB and FB. METHODS: Standard analytical procedures were used to determine the nutritional quality and GAR of PB and FB. RESULTS: The chemical analysis illustrated that functional profile (water holding capacity, oil holding capacity, swelling power, and solubility), and proximate (ash, moisture, protein, fat, dietary fiber, and carbohydrate) contents were substantially high in FB than PB. With a well-proportionate amino acid profile, PB (0.56) and FB (0.54) comprised of a high ratio of essential to nonessential amino acids than those of FAO/WHO requirement (0.38). The mineral analysis revealed that PB and FB were rich in macro and micro minerals in the order K > Ca > Mg > P > Na and K > Mg > Na > Ca > P, respectively. Linoleic acid was found to be the major component in PB and FB. Besides, total antioxidant activity conducted for PB and FB by GAR method, measuring both bio-accessible and insoluble fractions, revealed that the soluble fraction fared better than the chemical extracts. CONCLUSION: The results revealed high nutritional qualities of the byproducts of banana and the low cost of its production promotes their use as a prospective nonconventional food resource with high nutraceutical value. SUMMARY: AOAC: Association of Analytical CommunitiesFAO/WHO: Food and Agriculture Organization of the United Nations/World health organization Abbreviations Used: Banana flower was more potent than banana pseudostem in terms of its nutritional quality and total antioxidant capacity affirming their usefulness (of both the secondary products) in the pharmaceutical sector as a nutritional supplement due to the health-related properties of dietary fibre and associated bioactive compounds.

The effect of a plant extract enriched in stigmasterol and ß-sitosterol on glycaemic status and glucose metabolism in alloxan-induced diabetic rats.

Banana is an extensively cultivated plant worldwide, mainly for its fruit, while its ancillary product, the banana pseudostem, is consumed as a vegetable and is highly recommended for diabetics in the traditional Indian medicine system. The present study was aimed at elucidating the mechanism of antihyperglycaemia exerted by the ethanol extract of banana pseudostem (EE) and its isolated compounds viz., stigmasterol (C1) and ß-sitosterol (C2), in an alloxan-induced diabetic rat model. Diabetic rats which were administered with C1, C2 and EE (100 and 200 mg per kg b. wt.) for 4 weeks showed reduced levels of fasting blood glucose and reversal of abnormalities in serum/urine protein, urea and creatinine in diabetic rats compared to the diabetic control group of rats. Diabetic symptoms such as polyphagia, polydipsia, polyuria, urine glucose and reduced body weight were ameliorated in the diabetic group of rats fed with EE, C1 and C2 (100 mg per kg b. wt., once daily) for 28 days. The levels of insulin and Hb were also increased, while the HbA1c level was reduced. The altered activities of hepatic marker enzymes viz., aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP); glycolytic enzyme (hexokinase); shunt enzyme (glucose-6-phosphate dehydrogenase); gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase and lactate dehydrogenase) and pyruvate kinase were significantly reverted to normal levels by the administration of EE, C1 and C2. In addition, increased levels of hepatic glycogen and glycogen synthase and the corresponding decrease of glycogen phosphorylase activity in diabetic rats illustrated the antihyperglycaemic potential of EE and its components. The histological observations revealed a marked regeneration of the ß-cells in the drug treated diabetic rats. These findings suggest that EE might exert its antidiabetic potential in the presence of C1 and C2, attributable to the enhanced glycolytic activity, besides increasing the hepatic glucose utilization in diabetic rats by stimulating insulin secretion from the remnant ß-cells.