Design, synthesis, in-vitro biological profiling and molecular docking of some novel oxazolones and imidazolones exhibiting good inhibitory potential against acetylcholine esterase.

Heterocyclic compounds with oxazole and imidazole rings in their structure have disclosed momentous biological aptitudes. Taking into account their superlative attributes, the present study was designed to introduce a new synthetic scheme to make new derivatives with tremendous futuristic pharmacological potentialities. Series of Oxazolones were synthesized by using substituted benzaldehyde with benzyl halides to produce respective benzaldehyde derivatives 1 (a-d) which further reacted with hippuric acid to yield oxazolones 2 (a-e). Newly synthesized oxazolones then reacted with 4-chloroaniline to yield corresponding imidazolones 3 (a-e). All the compounds were characterized by using FTIR and NMR spectroscopic techniques. Docking studies of Compounds were conducted using AutoDock Vina and analyzed with PYMOL. All synthesized oxazolone and imidazolone derivatives exhibited antioxidant potential, demonstrated by their IC50 values compared to ascorbic acid standard. Oxazolone derivatives (2a-2e) exhibited good acetyl cholinesterase inhibitory potential whereas Imidazolone series did not show significant inhibition as shown by their IC50 values compared to donepezil as a standard. Docking studies of all compounds against acetylcholinesterase demonstrated favorable binding affinity, indicating their potential for further in-vivo studies. It is notable that novel compounds of both oxazolones and Imidazolone series exhibited antioxidant potential with maximum percentage inhibition of 75.9 (IC50 12.9 ± 0.0573 µM/mL) by compound 2d while compound 2a showed AChE inhibitory potential with maximum %age inhibition of 75.49 (IC50 7.8 ± 0.0218 µM/mL).Communicated by Ramaswamy H. Sarma.

Bioassay-guided isolation and in silico study of antihyperlipidemic compounds from Onosma hispidum Wall.

Isolation of bioactive compounds from plants and their therapeutic evaluation is crucial in the pursuit of novel phytochemicals and contributes an indispensable role in drug discovery and design. The literature has documented the hypolipidemic effect of numerous Onosma species. Taking that into consideration, the current study was designed to isolate, purify and evaluate the antihyperlipidemic potential of leaves of Onosma hispidum Wall. For the first time, the bioassay-guided isolation led to the separation of 3 compounds that were identified by spectroscopic techniques as o-phthalic acid bis-(2-ethyl decyl)-ester (1), bis (2-ethyloctyl) phthalate (2), and 1,2 benzenedicarboxylic acid bis(2-methyl heptyl) ester (3). Lipase inhibition assay was utilized to scrutinize the antihyperlipidemic potential of methanolic extract fractions and subsequently isolated compounds. Further, the isolated compounds were employed for in silico studies via molecular docking, molecular mechanics with generalized born and surface area solvation (MM-GBSA), and MD simulations with Pancreatic Lipase Colipase (PDB ID: 1LPB). Molecular docking and MM-GBSA of isolated compounds were employed to explain the mode of binding between the protein-ligand complex and binding free energy calculation, respectively. Since compound (3) displayed the best docking score of -6.689 kcal/mol as compared to orlistat -5.529 kcal/mol with PDB: 1LPB. So, it was chosen for MD simulations to evaluate ligand stability and flexibility of the complex which was validated by the fluctuation of α-carbon chain, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and type of interactions involved which authenticated the in vitro lipase inhibitory potential. Overall, in silico and in vitro results validated that compound (3) could be exploited as a promising pancreatic lipase inhibitor.Communicated by Ramaswamy H. Sarma.

Synthesis, Computational Studies, Antioxidant and Anti-Inflammatory Bio-Evaluation of 2,5-Disubstituted-1,3,4-Oxadiazole Derivatives.

The 1,3,4-oxadiazole derivatives Ox-6a-f have been synthesized by incorporating flurbiprofen moiety with the aim to explore the potential of target molecules to decrease the oxidative stress. The title compounds Ox-6a-f were prepared by simple reactions in which a flurbiprofen -COOH group was esterified with methanol in an acid-catalyzed medium, which was then reacted with hydrazine to afford the corresponding hydrazide. The acid hydrazide was then cyclized into 1,3,4-oxadiazole-2-thiol by reacting with CS2 in the presence of KOH. The title compounds Ox-6a-f were synthesized by the reaction of an -SH group with various alkyl/aryl chlorides, which involves an S-alkylation reaction. The structures of the synthesized Ox-6a-f derivatives were ascertained by spectroscopic data. The in silico molecular docking was performed against target proteins cyclooxygenase-2 COX-2 (PDBID 5KIR) and cyclooxygenase-1 COX-1 (PDBID 6Y3C) to determine the binding affinity of the synthesized compounds with these structures. It has been inferred that most of the synthesized compounds bind well with an active binding site of 5KIR compared to 6Y3C, and especially compound Ox-6f showed excellent binding affinity (7.70 kcal/mol) among all synthesized compounds Ox-6a-f. The molecular dynamic (MD) simulation has also been performed to check the stability of docking complexes of ligands with COX-2 by determining their root mean square deviation and root mean square fluctuation. Little fluctuation was observed in case of Ox-6f, which forms the most stable complex with COX-2. The comprehensive antioxidant potential of the synthesized compounds has been evaluated by determining their free radical scavenging activity, including DPPH, OH, nitric oxide (NO), and iron chelation assay. The derivative Ox-6f showed promising results with 80.23% radical scavenging potential at a dose of 100 µg/mL while ascorbic acid exhibited 87.72% inhibition at the same dose. The anti-inflammatory activity of the final products has also been performed, and inflammatory markers were assayed, such as a thiobarbituric acid-reducing substance, nitric oxide, interleukin-6 (IL-6), and COX-2. The derivatives Ox-6d and Ox-6f displayed higher anti-inflammatory activity, exhibiting 70.56% and 74.16% activity, respectively. The results were compared with standard ibuprofen, which showed 84.31% activity at the same dose, 200 µg/mL. The anti-inflammatory potential has been performed by following the carrageen-induced hind paw edema model, and results showed that derivative Ox-6f exhibited 79.83% reduction in edema volume compared to standard ibuprofen, which reduced 84.31% edema volume. As dry lab and wet lab results confirm each other, it has been deduced that derivative Ox-6f may serve as the lead structure to design potent compounds to address oxidative stress.

Assessment of the antidiabetic potential of extract and novel phytoniosomes formulation of Tradescantia pallida leaves in the alloxan-induced diabetic mouse model.

Diabetes inflicts health and economic burdens on communities and the present antidiabetic therapies have several drawbacks. Tradescantia pallida leaves have been used as a food colorant and food preservative; however, to our knowledge antidiabetic potential of the leaves of T. pallida has not been explored yet. The current study aimed to investigate the antidiabetic potential of T. pallida leaves extract and its comparison with the novel nisosome formulation of the extract. The leaves extract and phytoniosomes of T. pallida in doses of 15, 25 and 50 mg/kg were used to assess the oral glucose loaded, and alloxan-induced diabetic mice models. The biological parameters evaluated were; change in body weight, blood biochemistry, relative organ to body weight ratio and histopathology of the liver, pancreas and kidney. Results revealed that the extract 50 mg/kg and phytoniosomes 25 and 50 mg/kg remarkably reduced the blood glucose level in all hyperglycemic mice by possibly inhibiting α-amylase and α-glucosidase production. Body weight and blood biochemical parameters were considerably improved in phytoniosomes 50 mg/kg treated group. The relative body weight was similar to those of healthy mice in extract 50 mg/kg, phytoniosomes 25 mg/kg, and phytoniosomes 50 mg/kg treated groups. Histopathology showed the regeneration of cells in the CHN50 treated group. Hyphenated chromatographic analysis revealed potent metabolites, which confirmed the antidiabetic potential of the extract by inhibiting α-amylase and α-glucosidase using in silico analysis. The present data suggested that phytoniosomes have shown better antidiabetic potential than crude extract of these leaves.

Phenolic compounds from Tradescantia pallida ameliorate diabetes by inhibiting enzymatic and non-enzymatic pathways.

Diabetes is a chronic metabolic disorder marked by postprandial hyperglycemia due to several etiologies including abnormal carbohydrate digestion and glycation of hemoglobin. The prolong use of synthetic drugs results in characteristic side effects which necessitates the discovery of safe and cost-effective substitutes. The aim of the current study is to isolate and evaluate the antidiabetic potential of the phenolic compounds from the leaves of Tradescantia pallida. Syringic acid, p-coumaric acid, morin and catechin (compounds 1-4) were isolated and characterized from Tradescantia pallida leaves using column chromatography and spectroscopic techniques. The in vitro antidiabetic potential of the phenolic compounds were assessed using α-amylase and non-enzymatic glycosylation of hemoglobin protein assays. A mechanistic insight of interactions between phenolic compounds and human α-amylase and hemoglobin protein were scrutinized by employing molecular docking method. Prime Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations were carried out to find the binding energies of the ligand-protein complexes. Morin and catechin were further analyzed to find the dynamic and thermodynamic constraints of the complexes under specific biological conditions using molecular dynamic simulation trajectories. The stability and flexibility of the complexes were justified by fluctuation of α-carbon chain, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and type of interactions involved which authenticated the in vitro inhibitory potential of morin and catechin against enzymatic and non-enzymatic pathways. The current study could be fruitful in rational designing of safe antidiabetic drugs of natural origin.Communicated by Ramaswamy H. Sarma.

Prediction of α-Glucosidase Inhibitory Activity of LC-ESI-TQ-MS/MS-Identified Compounds from Tradescantia pallida Leaves.

Diabetes is a chronic disease that leads to abnormal carbohydrate digestion and hyperglycemia. The long-term use of marketed drugs results in secondary infections and side effects that demand safe and natural substitutes for synthetic drugs. The objective of this study is to evaluate the antidiabetic potential of compounds from the leaves of Tradescantia pallida. Thirteen phenolic compounds were identified from the ethyl acetate fraction of leaves of Tradescantia pallida using liquid chromatography-mass spectrometry. The compounds were then studied for the type of interactions between polyphenols and human α-glucosidase protein using molecular docking analysis. Prime Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations were performed to measure the binding free energies responsible for the formation of ligand-protein complexes. The compounds were further investigated for the thermodynamic constraints under a specified biological environment using molecular dynamic simulations. The flexibility of the ligand-protein systems was verified by Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and molecular interactions. The results authenticated the antidiabetic potential of polyphenols identified from the leaves of Tradescantia pallida. Our investigations could be helpful in the design of safe antidiabetic agents, but further in vitro and in vivo investigations are required.

Antihypertensive potential of Brassica rapa leaves: An in vitro and in silico approach.

Aim: Plants contain many essential constituents and their optimization can result in the discovery of new medicines. One such plant is Brassica rapa that is commonly used as a vegetable to fulfill daily food requirements worldwide. This study intends to screen the phytochemicals, antihypertensive potential, GC-MS, and in silico analysis of the leaves of Brassica rapa. Methods: Powdered leaves were subjected to proximate analysis followed by estimation of primary metabolites. Extracts were obtained by hot and cold extraction and investigated for secondary metabolites. All crude extracts were screened for their antihypertensive potential using an angiotensin-converting enzyme (ACE) inhibition assay. GC-MS analysis was carried out to standardize the extract, and an antihypertensive metabolite was confirmed using an in silico approach. Results: Physicochemical evaluation resulted in moisture content (9.10% ± 0.1), total ash value (18.10% ± 0.6), and extractive values (water 9.46% ± 0.5 and alcohol soluble 4.99% ± 0.1), while phytochemical investigation revealed primary metabolites (total proteins 11.90 mg/g ± 0.9; total fats 3.48 mg/g ± 0.5; and total carbohydrates 57.45 mg/g ± 1.2). Methanol extract showed the highest number of secondary metabolites including polyphenols 93.63 mg/g ± 0.6; flavonoids 259.13 mg/g ± 0.6; and polysaccharides 56.63 mg/g ± 1.4, while water extract (70 mg/g ± 2) was rich in glycosaponins. Methanol extract showed the highest antihypertensive potential by inhibiting ACE (79.39%) amongst all extracts, compared to the standard drug captopril, which inhibited 85.81%. Standardization of methanol extract via GC-MS analysis revealed potent phytoconstituents, and a molecular docking study confirmed that oleic acid is the main antihypertensive metabolite. Conclusion: We conclude that leaves of Brassica rapa can successfully lower hypertension by inhibiting ACE, however; in vivo investigations are required to confirm this antihypertensive activity.

A systematic review of RdRp of SARS-CoV-2 through artificial intelligence and machine learning utilizing structure-based drug design strategy.

Since the coronavirus disease has been declared a global pandemic, it had posed a challenge among researchers and raised common awareness and collaborative efforts towards finding the solution. Caused by severe acute respiratory coronavirus syndrome-2 (SARS-CoV-2), coronavirus drug design strategy needs to be optimized. It is understandable that cognizance of the pathobiology of COVID-19 can help scientists in the development and discovery of therapeutically effective antiviral drugs by elucidating the unknown viral pathways and structures. Considering the role of artificial intelligence and machine learning with its advancements in the field of science, it is rational to use these methods which can aid in the discovery of new potent candidates in silico. Our review utilizes similar methodologies and focuses on RNA-dependent RNA polymerase (RdRp), based on its importance as an essential element for virus replication and also a promising target for COVID-19 therapeutics. Artificial neural network technique was used to shortlist articles with the support of PRISMA, from different research platforms including Scopus, PubMed, PubChem, and Web of Science, through a combination of keywords. "English language", from the year "2000" and "published articles in journals" were selected to carry out this research. We summarized that structural details of the RdRp reviewed in this analysis will have the potential to be taken into consideration when developing therapeutic solutions and if further multidisciplinary efforts are taken in this domain then potential clinical candidates for RdRp of SARS-CoV-2 could be successfully delivered for experimental validations.

Investigations of Acacia modesta Wall. leaves for in vitro anti-diabetic, proliferative and cytotoxic effects

ABSTRACT The leaves of Acacia modesta Wall. have been shown to possess diverse pharmacological properties. Therefore, we aimed at evaluating anti-diabetic, cytotoxic and proliferative effects of extracts of Acacia modesta Wall. leaves. After evaluating the primary and secondary metabolites, anti-diabetic activity of various extracts was assessed by α-amylase inhibition, glucose uptake by yeast cells and non-enzymatic glycosylation of hemoglobin assay. Cytotoxicity and proliferative potential was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and short term proliferation assays, respectively, using human liver carcinoma cell line, HepG2. Among other extracts, chloroform extract exhibited 34.16% inhibition of α-amylase, 90.65% inhibition of hemoglobin glycosylation and 94.75% glucose uptake employing α-amylase inhibition, non-enzymatic glycosylation of hemoglobin and glucose uptake by yeast cells assays, respectively. Moreover, extracts exhibited no significant effects on HepG2 cell viability and proliferation. So, this data suggested that chloroform extract of leaves of Acacia modesta Wall., exhibited higher anti-hyperglycemic activity in comparison to extracts in other solvents, while no extract demonstrated cytotoxic and proliferation effects when tested using HepG2 cell line