Novel NO-TZDs and trimethoxychalcone-based DHPMs: design, synthesis, and biological evaluation as potential VEGFR-2 inhibitors.

Novel series of nitric oxide-releasing thiazolidine-2,4-diones (NO-TZD-3a-d,5,6) and 3,4,5-trimethoxychalcone-based multifunctional 1,4-dihydropyrimidines (CDHPM-10a-g) have been designed and synthesised as potent broad-spectrum anticancer agents with potential VEGFR-2 inhibition. The designed analogs were evaluated for their anticancer activities towards a full panel of NCI-60 tumour cell lines and CDHPM-10a-g emerged mean %inhibitions ranging from 76.40 to 147.69%. Among them, CDHPM-10e and CDHPM-10f demonstrated the highest MGI% of 147.69 and 140.24%, respectively. Compounds CDHPM-10a,b,d-f showed higher mean %inhibitory activity than the reference drug sorafenib (MGI% = 105.46%). Superiorly, the hybrid CDHPM-10e displayed the highest potencies towards all the herein tested subpanels of nine types of cancer with MGI50 of 1.83 µM. Also, it revealed potent cytostatic single-digit micromolar activity towards the herein examined cancer cell lines. The designed compounds CDHPM-10a-g were exposed as potent non-selective broad-spectrum anticancer agents over all NCI subpanels with an SI range of 0.66-1.97. In addition, the target analog CDHPM-10e revealed potency towards VEGFR-2 kinase comparable to that of sorafenib with a sub-micromolar IC50 value of 0.11 µM. Also, CDHPM-10e could effectively induce Sub-G1-phase arrest and prompt apoptosis via caspase and p53-dependent mechanisms. Furthermore, CDHPM-10e revealed significant anti-metastatic activity as detected by wound healing assay. The modelling study implies that CDHPM-10e overlaid well with sorafenib and formed a strong H-bond in the DFG binding domain. The ADMET studies hinted out that CDHPM-10e met Pfizer's drug-likeness criteria. The presented novel potent anticancer agent merits further devotion as a new lead product in developing more chalcone-based VEGFR-2 inhibitors.

Isolation, invitro, invivo anti-inflammatory, analgesic and antioxidant potential of Habenaria plantegania Lindl.

Habenaira plantaginea belong to orchid family which is native to Asia. Members of this family are commonly famous for the cure of pain and inflammation. To date, no research was found on isolation of compounds from this plant for the treatment of inflammation and analgesia nor has been published to our knowledge. The purpose of this study was to evaluate an analgesic, anti-inflammatory and anti-oxidant activity of the isolated compound from the most potent chloroform sub-fraction and the isolated compounds form the habenaria plantaginea. Anti-inflammatory analgesic and antioxidant potential of the various chloroform sub-fractions and isolated compounds from the most potent sub-fraction (HP-1 & HP-1) were screened for their in vitro enzymatic assays. Furthermore, prior to in-vivo investigation, the isolated compounds were subjected for their toxicity study. The potent compound was then examined for acetic acid-induced writhing, hot plate test, carrageenan-induced inflammation assays. Further various phlogistic agents were used for the evaluation of mechanism. In the COX-2 inhibitory assay the chloroform sub fraction Cf-4 demonstrated excellent activity as compared to the other sub-fraction with 92.15% inhibition. The COX-2 enzyme make prostaglandins which are directly involved in inflammation. Likewise against 5-LOX the Cf-4 was the most potent sub-fraction with IC50 3.77 µg/mL. The 5-LOX catalyzes the biosynthesis of leukotrienes which is a group of lipid mediators of inflammation derived from arachidonic acid. Free radicals can induce inflammation through cellular damage while chronic inflammation generates a large number of free radicals, whose eventually lead to inflammation. In antioxidant assays the Cf-4 fraction was displayed excellent results against ABTS, DPPH and H2O2 free radical with 88.88, 77.44, and 65.52% inhibition at highest concentration. Likewise, the compound HP-1 demonstrated 88.81, 89.34 and 80.43% inhibition while compound HP-2 displayed 84.34, 91.52 and 82.34% inhibition against ABTS, DPPH and H2O2 free radical which were comparable to the standard drug ascorbic acid respectively. This study's findings validate the use of this species as traditional use.

An innovative dual-signal electrochemical ratiometric determination of creatinine based on silver nanoparticles with intrinsic self-calibration property for bimetallic Prussian blue analogues.

An ultrasensitive dual-signal ratiometric electrochemical sensor was developed for creatinine detection utilizing silver nanoparticles (Ag) with intrinsic self-calibration afforded by iron-nickel bimetallic Prussian blue (FeNiPBA) analogues. The Ag@FeNiPBA exhibits two redox signals corresponding to the Ag+/Ag and Fe3+/Fe2+ systems. Adding chloride (Cl-) solution increases the anodic current of the Ag/Ag system significantly due to the formation of silver chloride through solid-state electrochemistry. While the anodic current of the Ag/Ag system decreases in the presence of creatinine due to the competitive reaction, the Fe/Fe system's anodic current remains the same, which enables a ratiometric response. Under optimized conditions, the response ratio (IAg/IFe) decreases while the creatinine concentration increases linearly between 0.015 and 140 µM, with 0.004 µM as a good detection limit (S/N = 3). These results demonstrate superior performance over previously reported methods for electrochemical creatinine determination. The high sensitivity arises from the signal amplification of the Ag/AgCl solid-state electrochemistry, while the selectivity originates from the specific interaction between Ag+ and creatinine. The Ag@FeNiPBA hybrid can quantify creatinine in real samples with good recoveries. This work opens up new opportunities for applying dual-signal nanostructures to develop electrochemical sensors for (bio)molecule detection.

Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors.

A novel series of multifunctional pyrazolo[3,4-d]pyrimidine-based glutamate analogs (6a-l and 7a,b) have been designed and synthesized as antifolate anticancer agents. Among the tested compounds, 6i exhibited the most potent anti-proliferative activity towards NSCLC, CNS, Ovarian, Prostate, Colon, Melanoma, Breast, and Renal cancers with good to weak cytostatic activity and non-lethal actions. 6i demonstrated higher selectivity for cancer than normal cells. 6i could significantly increase the accumulation of S-phase cells during the cell cycle distribution of cancer cells with high potency in the induction of apoptosis. The results unveiled that 6i probably acts through dual inhibition of DHFR and TS enzymes (IC50 = 2.41 and 8.88 µM, correspondingly). Docking studies of 6i displayed that N1-p-bromophenyl and C3-Methyl groups participate in substantial hydrophobic interactions. The drug-likeness features inferred that 6i met the acceptance criteria of Pfizer. Taking together, 6i could be a promising prototype for further optimization as an effective anticancer drug.

Novel EGFR-MAPK kinase and ABC transporter inhibitors for HepG2 resistant to Erlotinib.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer death in the world, with outlook for most patients having a 5-year survivability of less than 5%. In a previous study from our laboratory, novel estrone inspired analogs act as epidermal growth factor receptor (EGFR) inhibitors in HepG2 cells. This study focuses on the effect of these analogs on an HCC cell line resistance to Erlotinib. Lead compounds MMA132 and MMA102 showed 13 and 20 µM IC50 values, respectively against HepG2-R resistant to Erlotinib. These compounds showed cell cycle arrest of the G2 phase up to 54%, and inhibited cell migration of HepG2-R cells up to 48 h. Western blot analysis revealed that MMA132 reduced total EGFR content after 48 h, while MMA102 inhibited MEK kinase by 84% after 48 h. Western blot analysis also revealed that multidrug resistance protein 2 (MRP2) is overexpressed in HepG2-R, suggesting that ABC transporters play a likely cause in drug resistance. MMA102 showed significant inhibition of both P-glycoprotein (83%) and ABCG2 (53%), two additional ABC transporters. Additionally, MMA102 and MMA132 were used in a combination therapy with MK571(MRP1/2 inhibitor) and produced IC50 values of 18 and 10 µM, respectively, better than either MMA102/132 or MK571 alone. To validate our findings, we conducted molecular dynamic simulations with MMA102 and MMA132 in MEK, P-glycoprotein, MRP1, and MRP2. Results coincided with biological findings in which MMA102 orientation is favored in both MEK and P-glycoprotein pockets, whereas MMA132 likely binds with MRP2, as likely suggested by the combinatorial study.

Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches.

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3's ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC50 value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy.

Deacetylated Sialic Acid Sensitizes Lung and Colon Cancers to Novel Cucurbitacin-Inspired Estrone Epidermal Growth Factor Receptor (EGFR) Inhibitor Analogs.

Cancers utilize sugar residues such as sialic acids (Sia) to improve their ability to survive. Sia presents a variety of functional group alterations, including O-acetylation on the C6 hydroxylated tail. Previously, sialylation has been reported to suppress EGFR activation and increase cancer cell sensitivity to Tyrosine Kinase Inhibitors (TKIs). In this study, we report on the effect of deacetylated Sia on the activity of three novel EGFR-targeting Cucurbitacin-inspired estrone analogs (CIEAs), MMA 294, MMA 321, and MMA 320, in lung and colon cancer cells. Acetylation was modulated by the removal of Sialate O-Acetyltransferase, also known as CAS1 Domain-containing protein (CASD1) gene via CRISPR-Cas9 gene editing. Using a variety of cell-based approaches including MTT cell viability assay, flow cytometry, immunofluorescence assay and in-cell ELISA we observed that deacetylated Sia-expressing knockout cells (1.24-6.49 µM) were highly sensitive to all CIEAs compared with the control cells (8.82-20.97 µM). Apoptosis and varied stage cell cycle arrest (G0/G1 and G2/M) were elucidated as mechanistic modes of action of the CIEAs. Further studies implicated overexpression of CIEAs' cognate protein target, phosphorylated EGFR, in the chemosensitivity of the deacetylated Sia-expressing knockout cells. This observation correlated with significantly decreased levels of key downstream proteins (phosphorylated ERK and mTOR) of the EGFR pathway in knockout cells compared with controls when treated with CIEAs. Collectively, our findings indicate that Sia deacetylation renders lung and colon cancer cells susceptible to EGFR therapeutics and provide insights for future therapeutic interventions.

In Silico Study on the Interactions, Molecular Docking, Dynamics and Simulation of Potential Compounds from Withania somnifera (L.) Dunal Root against Cancer by Targeting KAT6A.

Cancer is characterized by the abnormal development of cells that divide in an uncontrolled manner and further take over the body and destroy the normal cells of the body. Although several therapies are practiced, the demand and need for new therapeutic agents are ever-increasing because of issues with the safety, efficacy and efficiency of old drugs. Several plant-based therapeutics are being used for treatment, either as conjugates with existing drugs or as standalone formulations. Withania somnifera (L.) Dunal is a highly studied medicinal plant which is known to possess immunomodulatory activity as well as anticancer properties. The pivotal role of KAT6A in major cellular pathways and its oncogenic nature make it an important target in cancer treatment. Based on the literature and curated datasets, twenty-six compounds from the root of W. somnifera and a standard inhibitor were docked with the target KAT6A using Autodock vina. The compounds and the inhibitor complexes were subjected to molecular dynamics simulation (50 ns) using Desmond to understand the stability and interactions. The top compounds (based on the docking score of less than -8.5 kcal/mol) were evaluated in comparison to the inhibitor. Based on interactions at ARG655, LEU686, GLN760, ARG660, LEU689 and LYS763 amino acids with the inhibitor WM-8014, the compounds from W. somnifera were evaluated. Withanolide D, Withasomniferol C, Withanolide E, 27-Hydroxywithanone, Withanolide G, Withasomniferol B and Sitoindoside IX showed high stability with the residues of interest. The cell viability of human breast cancer MCF-7 cells was evaluated by treating them with W. Somnifera root extract using an MTT assay, which showed inhibitory activity with an IC50 value of 45 µg/mL. The data from the study support the traditional practice of W. somnifera as an anticancer herb.

New Succinimide-Thiazolidinedione Hybrids as Multitarget Antidiabetic Agents: Design, Synthesis, Bioevaluation, and Molecular Modelling Studies.

Diabetes mellitus (DM) is a metabolic disorder majorly arising from the pathophysiology of the pancreas manifested as a decline in the insulin production or the tissue's resistance to the insulin. In this research, we have rationally designed and synthesized new succinimide-thiazolidinedione hybrids for the management of DM. In a multistep reaction, we were able to synthesize five new derivatives (10a-e). All the compounds were new containing a different substitution pattern on the N-atom of the succinimide ring. Initially, all the compounds were tested against the in vitro α-glucosidase, α-amylase, PTP1B, and DPP4 targets. In all of these targets, the compound 10d was observed to be the most potential antidiabetic agent. Based on this, the antidiabetic activity of the compound 10d was further investigated in experimental animals, which overall gave us encouraging results. The molecular docking studies of the compound 10d was also performed against the target enzymes α-glucosidase, α-amylase, PTP1B, and DPP4 using MOE. Overall, we observed that we have explored a new class of compounds as potential antidiabetic agents.

Exploring the Potential of Phytocompounds for Targeting Epigenetic Mechanisms in Rheumatoid Arthritis: An In Silico Study Using Similarity Indexing.

Finding structurally similar compounds in compound databases is highly efficient and is widely used in present-day drug discovery methodology. The most-trusted and -followed similarity indexing method is Tanimoto similarity indexing. Epigenetic proteins like histone deacetylases (HDACs) inhibitors are traditionally used to target cancer, but have only been investigated very recently for their possible effectiveness against rheumatoid arthritis (RA). The synthetic drugs that have been identified and used for the inhibition of HDACs include SAHA, which is being used to inhibit the activity of HDACs of different classes. SAHA was chosen as a compound of high importance as it is reported to inhibit the activity of many HDAC types. Similarity searching using the UNPD database as a reference identified aglaithioduline from the Aglaia leptantha compound as having a ~70% similarity of molecular fingerprints with SAHA, based on the Tanimoto indexing method using ChemmineR. Aglaithioduline is abundantly present in the shell and fruits of A. leptantha. In silico studies with aglaithioduline were carried out against the HDAC8 protein target and showed a binding affinity of -8.5 kcal mol. The complex was further subjected to molecular dynamics simulation using Gromacs. The RMSD, RMSF, compactness and SASA plots of the target with aglaithioduline, in comparison with the co-crystallized ligand (SAHA) system, showed a very stable configuration. The results of the study are supportive of the usage of A. leptantha and A. edulis in Indian traditional medicine for the treatment of pain-related ailments similar to RA. Our study therefore calls for further investigation of A. leptantha and A. edulis for their potential use against RA by targeting epigenetic changes, using in vivo and in vitro studies.

Preparation, Characterization and Evaluation of Flavonolignan Silymarin Effervescent Floating Matrix Tablets for Enhanced Oral Bioavailability.

The convenient and highly compliant route for the delivery of active pharmaceutical ingredients is the tablet. A versatile platform of tablets is available for the delivery of therapeutic agents to the gastrointestinal tract. This study aimed to prepare gastro retentive drug delivery floating tablets of silymarin to improve its oral bioavailability and solubility. Hydroxypropyl methylcellulose (HPMCK4M and HPMCK15), Carbopol 934p and sodium bicarbonate were used as a matrix, floating enhancer and gas generating agent, respectively. The prepared tablets were evaluated for physicochemical parameters such as hardness, weight variation, friability, floating properties (floating lag time, total floating time), drug content, stability study, in vitro drug release, in vivo floating behavior and in vivo pharmacokinetics. The drug-polymer interaction was studied by Differential Scanning Calorimetry (DSC) thermal analysis and Fourier transform infrared (FTIR). The floating lag time of the formulation was within the prescribed limit (<2 min). The formulation showed good matrix integrity and retarded the release of drug for >12 h. The dissolution can be described by zero-order kinetics (r2 = 0.979), with anomalous diffusion as the release mechanism (n = 0.65). An in vivo pharmacokinetic study showed that Cmax and AUC were increased by up to two times in comparison with the conventional dosage form. An in vivo imaging study showed that the tablet was present in the stomach for 12 h. It can be concluded from this study that the combined matrix system containing hydrophobic and hydrophilic polymers min imized the burst release of the drug from the tablet and achieved a drug release by zero-order kinetics, which is practically difficult with only a hydrophilic matrix. An in vivo pharmacokinetic study elaborated that the bioavailability and solubility of silymarin were improved with an increased mean residence time.

Juglone from Walnut Produces Cardioprotective Effects against Isoproterenol-Induced Myocardial Injury in SD Rats.

Therapeutic and/or preventive interventions using phytochemical constituents for ischemic heart disease have gained considerable attention worldwide, mainly due to their antioxidant activity. This study investigated the cardioprotective effect and possible mechanism of juglone, a major constituent of the walnut tree, using an isoproterenol (ISO)-induced myocardial infarction (MI) model in rats. Rats were pretreated for five (5) days with juglone (1, 3 mg/kg, i.p) and atenolol (1 mg/kg, i.p) in separate experiments before inducing myocardial injury by administration of ISO (80 mg/kg, s.c) at an interval of 24 h for 2 consecutive days (4th and 5th day). The cardioprotective effect of juglone was confirmed through a lead II electrocardiograph (ECG), cardiac biomarkers (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological study. The results of our present study suggest that prior administration of juglone (1 and 3 mg/kg) proved to be effective as a cardioprotective therapeutic agent in reducing the extent of myocardial damage (induced by ISO) by fortifying the myocardial cell membrane, preventing elevated T-waves, deep Q-waves in the ECG, heart to body weight ratio, infarction and also by normalizing cardiac marker enzymes (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological changes, such as inflammation, edema and necrosis. In conclusion, this study has identified phytochemical constituents, in particular juglone, as a potential cardioprotective agent.

Design, synthesis, in-vitro, in-vivo and ex-vivo pharmacology of thiazolidine-2,4-dione derivatives as selective and reversible monoamine oxidase-B inhibitors.

Neurodegenerative ailments are a diverse set of syndromes distinguished by gradual deterioration of the structure as well as functions of the central nervous system or peripheral nervous system. Alzheimer's disease (AD) and Parkinson's disease (PD) have no cure, common, and are high prevalent neurodegenerative pathologies. In current research, rationally designed thiazolidine-2,4-dione based analogs were synthesized and tested for their inhibition potential against two isoforms of monoamine oxidase (MAO-A / MAO-B). Structure activity relationships were explored. Pyridinyl and thiazolyl hydrazone derivative 43 and 44 with IC50 value of 0.013 µM and 0.008 µM (selectivity 228 / 226 times) exhibited higher potency than reference drug safinamide. Most active compounds showed BBB penetration in PAMPA in-vitro assay. Except nitro derivative 41, all compounds were non-neurotoxic in the studied concentration. Molecular docking studies supported the in-vitro experimental results and the selectivity by comparing the binding energy values against both MAO-A and MAO-B isoforms. All the results of current research suggest compounds 43 and 44 may serve as promising candidates for further research for treatment of neurodegenerative diseases.

Bacillus subtilis: As an Efficient Bacterial Strain for the Reclamation of Water Loaded with Textile Azo Dye, Orange II.

The azo dye orange II is used extensively in the textile sector for coloring fabrics. High concentrations of it are released into aqueous environments through textile effluents. Therefore, its removal from textile wastewater and effluents is necessary. Herein, initially, we tested 11 bacterial strains for their capabilities in the degradation of orange II dye. It was revealed in the preliminary data that B. subtilis can more potently degrade the selected dye, which was thus used in the subsequent experiments. To achieve maximum decolorization, the experimental conditions were optimized whereby maximum degradation was achieved at: a 25 ppm dye concentration, pH 7, a temperature of 35 °C, a 1000 mg/L concentration of glucose, a 1000 mg/L urea concentration, a 666.66 mg/L NaCl concentration, an incubation period of 3 days, and with hydroquinone as a redox mediator at a concentration of 66.66 mg/L. The effects of the interaction of the operational factors were further confirmed using response surface methodology, which revealed that at optimum conditions of pH 6.45, a dye concentration of 17.07 mg/L, and an incubation time of 9.96 h at 45.38 °C, the maximum degradation of orange II can be obtained at a desirability coefficient of 1, estimated using the central composite design (CCD). To understand the underlying principles of degradation of the metabolites in the aliquot mixture at the optimized condition, the study steps were extracted and analyzed using GC-MS(Gas Chromatography Mass Spectrometry), FTIR(Fourier Transform Infrared Spectroscopy), 1H and carbon 13 NMR(Nuclear Magnetic Resonance Spectroscopy). The GC-MS pattern revealed that the original dye was degraded into o-xylene and naphthalene. Naphthalene was even obtained in a pure state through silica gel column isolation and confirmed using 1H and 13C NMR spectroscopic analysis. Phytotoxicity tests on Vigna radiata were also conducted and the results confirmed that the dye metabolites were less toxic than the parent dye. These results emphasize that B. subtilis should be used as a potential strain for the bioremediation of textile effluents containing orange II and other toxic azo dyes.

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain.

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1ß) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent.

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC50 values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.

α-Glucosidase, α-Amylase and Antioxidant Evaluations of Isolated Bioactives from Wild Strawberry.

Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and evaluate antidiabetic bioactives from Fragaria indica. The crude extracts, semi-purified and pure bioactives have been used in all in vitro assays. The in vitro α-glucosidase, α-amylase and DPPH free radical activities have been performed on all plant samples. The initial activities showed that ethyl acetate (Fi.EtAc) was the potent fraction in all the assays. This fraction was initially semi-purified to obtain Fi.EtAc 1-3. Among the semi-purified fractions, Fi.EtAc 2 was dominant, exhibiting potent IC50 values in all the in vitro assays. Based on the potency and availability of materials, Fi.EtAc 2 was subjected to further purification to obtain compounds 1 (2,4-dichloro-6-hydroxy-3,5-dimethoxytoluene) and 2 (2-methyl-6-(4-methylphenyl)-2-hepten-4-one). The two isolated compounds were characterized by mass and NMR analyses. The compounds 1 and 2 showed excellent inhibitions against α-glucosidase (21.45 for 1 and 15.03 for 2 µg/mL), α-amylase (17.65 and 16.56 µg/mL) and DPPH free radicals (7.62 and 14.30 µg/mL). Our study provides baseline research for the antidiabetic bioactives exploration from Fragaria indica. The bioactive compounds can be evaluated in animals-based antidiabetic activity in future.

Biological Evaluation, Phytochemical Screening, and Fabrication of Indigofera Linifolia Leaves Extract-Loaded Nanoparticles.

Indigofera linifolia is a medicinally important plant, and by virtue of its rich phytochemical composition, this plant is widely used as essential component in traditional medication systems. Due to its wide range of medicinal applications, the extract-loaded chitosan (Ext+Ch), extract-loaded PEG (Ext+PEG), and extract-loaded locust bean gum (Ext+LGB) nanoparticles (NPs) were prepared in the present study. The prepared NPs were then evaluated for their antibacterial, antioxidant, and antidiabetic potentials. Antibacterial activities of the crude extract and the synthesized NPs were performed following standard procedures reported in the literature. The antioxidant capabilities of extract and NPs were evaluated using DPPH free radical scavenging assay. The antidiabetic potential of the samples was evaluated against α-amylase and α-glucosidase. Ext+PEG NPs showed more potent antibacterial activity against the selected strains of bacteria with the highest activity against Escherichia coli. The lowest antibacterial potential was observed for Ext+LGB NPs. The Ext+LGB NPs IC50 value of 39 µg/mL was found to be the most potent inhibitor of DPPH free radicals. Ext+LGB NPs showed a greater extent of inhibition against α-glucosidase and α-amylase with an IC50 of 83 and 78 µg/mL, whereas for the standard acarbose the IC50 values recorded against the mentioned enzymes were 69 and 74 µg/mL, respectively. A high concentration of phenolics and flavonoids in the crude extract was confirmed through TPC and TFC tests, HPLC profiling, and GC-MS analysis. It was considered that the observed antibacterial, antidiabetic, and antioxidant potential might be due the presence of these phenolics and flavonoids detected. The plant could thus be considered as a potential candidate to be used as a remedy of the mentioned health complications. However, further research in this regard is needed to isolate the exact responsible compounds of the observed biological potentials exhibited by the crude extract. Further, toxicity and pharmacological evaluations in animal models are also needed to establish the safety or toxicity profile of the plant.

Anti-Inflammatory, Analgesic and Antioxidant Potential of New (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals and Their Corresponding Carboxylic Acids through In Vitro, In Silico and In Vivo Studies.

In the current study, a series of new (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals (FM1-6) with their corresponding carboxylic acid analogues (FM7-12) has been synthesized. Initially, the aldehydic derivatives were isolated in the diastereomeric form, and the structures were confirmed with NMR, MS and elemental analysis. Based on the encouraging results in in vitro COX 1/2, 5-LOX and antioxidant assays, we oxidized the compounds and obtained the pure single (major) diastereomer for activities. Among all the compounds, FM4, FM10 and FM12 were the leading compounds based on their potent IC50 values. The IC50 values of compounds FM4, FM10 and FM12 were 0.74, 0.69 and 0.18 µM, respectively, in COX-2 assay. Similarly, the IC50 values of these three compounds were also dominant in COX-1 assay. In 5-LOX assay, the majority of our compounds were potent inhibitors of the enzyme. Based on the potency and safety profiles, FM10 and FM12 were subjected to the in vivo experiments. The compounds FM10 and FM12 were observed with encouraging results in in vivo analgesic and anti-inflammatory models. The molecular docking studies of the selected compounds show binding interactions in the minimized pocked of the target proteins. It is obvious from the overall results that FM10 and FM12 are potent analgesic and anti-inflammatory agents.

In Silico Molecular Docking and Simulation Studies of Protein HBx Involved in the Pathogenesis of Hepatitis B Virus-HBV.

Current drug discovery involves finding leading drug candidates for further development. New scientific approaches include molecular docking, ADMET studies, and molecular dynamic simulation to determine targets and lead compounds. Hepatitis B is a disease of concern that is a life-threatening liver infection. The protein considered for the study was HBx. The hepatitis B X-interacting protein crystal structure was obtained from the PDB database (PDB ID-3MSH). Twenty ligands were chosen from the PubChem database for further in silico studies. The present study focused on in silico molecular docking studies using iGEMDOCK. The triethylene glycol monoethyl ether derivative showed an optimum binding affinity with the molecular target HBx, with a high negative affinity binding energy of -59.02 kcal/mol. Lipinski's rule of five, Veber, and Ghose were followed in subsequent ADMET studies. Molecular dynamic simulation was performed to confirm the docking studies and to analyze the stability of the structure. In these respects, the triethylene glycol monoethyl ether derivative may be a promising molecule to prepare future hepatitis B drug candidates. Substantial research effort to find a promising drug for hepatitis B is warranted in the future.