Self-healable, Tolerant Superaerophobic Coating for Improving Electrochemical Hydrogen Production.

Gas-evolving electrodes often suffer from the blocking of catalytic active sites-due to unwanted and unavoidable adhesion of generated gas bubbles, which elevates the overpotential for the electrochemical hydrogen evolution reaction (HER)- by raising the resistance of the electrode. Here, a catalyst-free and self-healable superaerophobic coating having ultra-low bubble adhesion is introduced for achieving significantly depleted overpotentials of 209 and 506 mV at both low (50 mA cm-2) and high (500 mA cm-2) current densities, respectively, compared to a bare nickel-foam electrode. The optimized coating ensured an early detachment of the generated tiny (0.8 ± 0.1 mm) gas bubble-and thus, prevented the undesired rise in resistance of the coated electrode. The systematic association of physical (i.e., ionic interactions, H-bonding, etc.) cross-linkage, ß-amino ester type covalent cross-linkage and reinforced halloysite nano clay enables the design of such functional material embedded with essential characteristics-including improved mechanical (toughness of 63.7 kJ m-3, and tensile modulus of 26 kPa) property and chemical (extremes of pH (1 and 14), salinity, etc.) stability, rapid (<10 min) self-healing ability (even at alkaline condition) and desired bubble-wettability (bubble contact angle of 158.2 ± 0.2°) with ultralow force (4.2 ± 0.4 µN) of bubble adhesion.

Molecular dynamics articulated multilevel virtual screening protocol to discover novel dual PPAR α/γ agonists for anti-diabetic and metabolic applications.

PPARα and PPARγ are isoforms of the nuclear receptor superfamily which regulate glucose and lipid metabolism. Activation of PPARα and PPARγ receptors by exogenous ligands could transactivate the expression of PPARα and PPARγ-dependent genes, and thereby, metabolic pathways get triggered, which are helpful to ameliorate treatment for the type 2 diabetes mellitus, and related metabolic complications. Herein, by understanding the structural requirements for ligands to activate PPARα and PPARγ proteins, we developed a multilevel in silico-based virtual screening protocol to identify novel chemical scaffolds and further design and synthesize two distinct series of glitazone derivatives with advantages over the classical PPARα and PPARγ agonists. Moreover, the synthesized compounds were biologically evaluated for PPARα and PPARγ transactivation potency from nuclear extracts of 3T3-L1 cell. Furthermore, glucose uptake assay on L6 cells confirmed the potency of the synthesized compounds toward glucose regulation. Percentage lipid-lowering potency was also assessed through triglyceride estimate from 3T3-L1 cell extracts. Results suggested the ligand binding mode was in orthosteric fashion as similar to classical agonists. Thus molecular docking and molecular dynamics (MD) simulation experiments were executed to validate our hypothesis on mode of ligands binding and protein complex stability. Altogether, the present study developed a newer protocol for virtual screening and enables to design of novel glitazones for activation of PPARα and PPARγ-mediated pathways. Accordingly, present approach will offer benefit as a therapeutic strategy against type 2 diabetes mellitus and associated metabolic complications.

Identification of benzothiazole-rhodanine derivatives as α-amylase and α-glucosidase inhibitors: Design, synthesis, in silico, and in vitro analysis.

A novel series of benzothiazole-rhodanine derivatives (A1-A10) were designed and synthesized, with the aim of developing possible antidiabetic agents and the spectral characterization of these compounds was done using infrared spectroscopy (IR), proton-nuclear magnetic resonance (1 H-NMR), carbon-nuclear magnetic resonance (C13 -NMR), and high resolution mass spectroscopy (HR-MS) techniques. In vitro hypoglycemic potential of the compounds was evaluated by performing α-amylase and α-glucosidase enzyme inhibitory assays. In addition, these compounds were subjected to in silico analysis. Based on the results, compounds A5, A6, and A9 displayed good activity in comparison with the standard acarbose. Based on Lineweaver-Burk plots, it was concluded that compounds A5 and A9 displayed competitive type of enzyme inhibition. Molecular dynamic simulations were conducted to evaluate the stability of the ligand-protein complex by the calculation of the root mean square deviation, root means square fluctuation, and solvent accessible surface area.

Impact of Counteranion on Reversible Spin-State Switching in a Series of Cobalt(II) Complexes Containing a Redox-Active Ethylenedioxythiophene-Based Terpyridine Ligand.

The self-assembly of a redox-active ethylenedioxythiophene (EDOT)-terpyridine-based tridentate ligand and cobalt(II) unit with different counteranions has led to a series of new cobalt(II) complexes [Co(L)2](X)2 (X = BF4 (1), ClO4 (2), and BPh4 (3)) (L = 4'-(3,4-ethylenedioxythiophene)-2,2':6',2″-terpyridine). The impact of various counteranions on stabilization and spin-state switching of the cobalt(II) center was explored through detailed magneto-structural investigation using variable temperature single-crystal X-ray diffraction, magnetic, spectroscopic, electrochemical, and spectroelectrochemical studies. All three complexes 1-3 consisted of an isostructural dicationic distorted octahedral CoN6 coordination environment offered by the two L ligands in a bis-meridional fashion and BF4-, ClO4-, and BPh4- as a counteranion, respectively. Complex 2 with ClO4- counteranion showed a reversible, gradual, and nearly complete spin-state switching between low-spin (LS) (S = 1/2) and high-spin (HS) (S = 3/2) states, while an incomplete spin-state switching behavior was observed for complexes 1 (BF4-) and 3 (BPh4-) in the measured temperature range of 350-2 K. The non-covalent cation-anion interactions played a significant role in stabilizing the spin-state in 1-3. Additionally, complexes 1-3 also exhibited interesting redox-stimuli-based reversible paramagnetic HS cobalt(II) (S = 3/2) to diamagnetic LS cobalt(III) (S = 0) conversion, offering an alternate way to switch the magnetic properties.

A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in Skeletal Muscle Cells via AMPK-Dependent Signaling.

INTRODUCTION: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are highly effective in treating insulin resistance. However, associated side effects such as weight gain due to increase in adipogenesis and lipogenesis hinder their clinical use. The aim of the study was to design and synthesize novel partial PPARγ agonists with weaker lipogenic effect in adipocytes and enhanced glucose transporter 4 (GLUT4) translocation stimulatory effect in skeletal muscle cells. METHODS: Novel partial PPARγ agonists (GS1, GS2, and GS3) were designed and screened to predict their binding interactions with PPARγ by molecular docking. The stability of the docked ligand-PPARγ complex was studied by molecular dynamics (MD) simulation. The cytotoxicity of synthesized compounds was tested in 3T3-L1 adipocytes and L6 myoblasts by MTT assay. The lipogenic effect was investigated in 3T3-L1 adipocytes using oil red O staining and GLUT4 translocation stimulatory effect in L6-GLUT4myc myotubes by an antibody-coupled colorimetric assay. RESULTS: The molecular docking showed the binding interactions between designed agonists and PPARγ. MD simulation demonstrated good stability between the GS2-PPARγ complex. GS2 and GS3 did not show any significant effect on cell viability up to 80 or 100 µM concentration. Pioglitazone treatment significantly increased intracellular lipid accumulation in adipocytes compared to control. However, this effect was significantly less in GS2- and GS3-treated conditions compared to pioglitazone at 10 µM concentration, indicating weaker lipogenic effect. Furthermore, GS2 significantly stimulated GLUT4 translocation to the plasma membrane in a dose-dependent manner via the AMPK-dependent signaling pathway in skeletal muscle cells. CONCLUSION: GS2 may be a promising therapeutic agent for the treatment of insulin resistance and type 2 diabetes mellitus without adiposity.

Bioanalytical chiral chromatographic technique and docking studies for enantioselective separation of meclizine hydrochloride: Application to pharmacokinetic study in rabbits.

Enantiomeric resolution and molecular docking studies of meclizine hydrochloride on polysaccharide-based chiral stationary phase comprising cellulose tris(4-methylbenzoate) chiral selector (150 × 4.6 mm, 3.0 µm) were presented. The mobile phase used was acetonitrile:10mM ammonium bicarbonate (95:05, v/v). The developed technique was used to perform the enantioselective assay of meclizine hydrochloride in its marketed formulation. The elution order of meclizine hydrochloride enantiomers was determined by docking studies. Target compound was extracted from rabbit plasma using protein precipitation technique, followed by development of bioanalytical chiral separation method using the same matrix. Application of the method to determine pharmacokinetic parameters of meclizine hydrochloride enantiomers was performed using Phoenix WinNonlin 8.1 software. The results demonstrated stereoselective disposition of meclizine hydrochloride enantiomers in rabbits.

Anticancer potential of novel symmetrical and asymmetrical dihydropyridines against breast cancer via EGFR inhibition: molecular design, synthesis, analysis and screening.

A series of novel symmetrical and asymmetrical dihydropyridines (HD 1-15) were designed, subjected to in silico ADMET prediction, synthesized, analyzed by IR, NMR, Mass analytical techniques and evaluated against epidermal growth factor receptor (EGFR) as inhibitors against Breast cancer. The results of predicted ADMET studies demonstrated the drug-likeness properties of the reported compounds. The in vitro cytotoxicity assessment of the synthesized compounds revealed that all of them showed good activity (IC50 ranging from 16.75 to 66.54 µM) towards MCF-7 breast cancer cells compared to the standard drug, Lapatinib (IC50 = 2.02 µM). Among these, compounds HD-6, HD-7, and HD-8 displayed the most potent activity with IC50 value of 21.26, 16.75, and 18.33 µM, respectively. Cytotoxicity of all compounds was tested on normal vero cells for comparison at different concentrations using the MTT assay. In addition to the MTT assay, the potent dihydropyridines derivatives were screened for EGFRwt kinase inhibition assay at concentrations ranging from 1 nM to 360 nM. Among the three compounds tested, HD-8 showed reasonably good inhibition with an IC50 value of 15.90 ± 1.20 nM compared to a standard Lapatinib IC50 value of 10.28 ± 1.01 nM. Based on the molecular docking study against EGFR, the most active derivatives HD-7 and HD-8 were docked against the active site of the protein and showed better binding affinity than the standard lapatinib. Additionally, molecular dynamics (MD) simulations were performed to explore the stability of the protein-ligand complex, its dynamic behavior, and the binding affinity.

Spin-state switching: chemical modulation and the impact of intermolecular interactions in manganese(III) complexes.

A series of mononuclear manganese(III) complexes [Mn(X-sal2-323)](ReO4) (X = 5 Cl, 1; X = 5 Br, 2; X = 3,5 Cl, 3; X = 3,5 Br, 4; and X = 5 NO2, 5), containing hexadentate ligands prepared using the condensation of N,N'-bis(3-aminopropyl)ethylenediamine and 5- or 3,5-substituted salicylaldehyde, has been synthesized. Variable temperature single-crystal X-ray diffraction, magnetic, spectroscopic, electrochemical, and spectroelectrochemical analyses, and theoretical calculations have been used to explore the role of various ligand substituents in the spin-state switching behavior of the prepared manganese(III) complexes. All five complexes consist of an analogous distorted octahedral monocationic MnN4O2 surrounding offered by the flexible hexadentate ligand and ReO4- as the counter anion. However, a disordered water molecule was detected in complex 4. Complexes 1 (X = 5 Cl) and 5 (X = 5 NO2) show gradual and complete spin-state switching between the high-spin (HS) (S = 2) and the low-spin (LS) (S = 1) state with T1/2 values of 146 and 115 K respectively, while an abrupt and complete transition at 95 K was observed for complex 2 (X = 5 Br). Alternatively, complex 3 (X = 3, 5 Cl) exhibits an incomplete and sharp transition between the HS and LS states at 104 K, while complex 4 (X = 3, 5 Br) (desolvated) remains almost LS up to 300 K and then displays gradual and incomplete SCO at a higher temperature. The nature of the spin-state switch and transition temperature suggest that the structural effect (cooperativity) plays a more significant role in comparison with the electronic effect coming from various substituents (Cl, Br, and NO2), which is further supported by the detailed structural, electrochemical, and theoretical studies.

Screening fructosamine-3-kinase (FN3K) inhibitors, a deglycating enzyme of oncogenic Nrf2: Human FN3K homology modelling, docking and molecular dynamics simulations.

Fructosamine-3-kinase (FN3K) is involved in the deglycation of Nrf2, a significant regulator of oxidative stress in cancer cells. However, the intricate functional aspects of FN3K and Nrf2 in breast cancers have not been explored vividly. The objectives of this study are to design the human FN3K protein using homology modeling followed by the screening of several anticancer molecules and examining their efficacy to modulate FN3K activity, Nrf2-mediated antioxidant signalling. Methods pertinent to homology modeling, virtual screening, molecular docking, molecular dynamics simulations, assessment of ADME properties, cytotoxicity assays for anticancer molecules of natural/synthetic origin in breast cancer cells (BT-474, T-47D), and Western blotting were used in this study. The screened anticancer molecules including kinase inhibitors of natural and synthetic origin interacted with the 3-dimensional structure of the catalytic domain in human FN3K protein designed through homology modeling by significant CDOCKER interaction energies. Subsequently, gefitinib, sorafenib, neratinib, tamoxifen citrate, and cyclosporine A enhanced the expression of FN3K in BT-474 cell lines with simultaneous alteration in Nrf2-driven antioxidant signalling. Oxaliplatin significantly downregulated FN3K expression and modulated Nrf2-driven antioxidant signalling when compared to cisplatin and other anticancer drugs. Hence, the study concluded the potential implications of existing anticancer drugs to modulate FN3K activity in breast cancers.

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.

Stearic acid mediated growth of edge-on oriented bilayer poly(3-hexylthiophene) Langmuir films.

The growth and structural evolution of stearic acid (SA) blended poly(3-hexylthiophene) [P3HT] Langmuir and Langmuir-Blodgett (LB) films were studied using complimentary surface and interface sensitive techniques to understand the possibility of ordering and layering of promising charge carrier mobility polymers, at the air-water interface and on the transferred solid substrate. SA-induced and subsequent compression-induced transitions in P3HT structure, from aggregated-3D to soft-2D and from in-plane mixed to unmixed layer, are evident at low and high pressures, respectively. The blending of SA molecules enhances the amphiphilic character of P3HT, which reduces the extent of the out-of-plane aggregation to form edge-on oriented (EO) bottom side-chain folded-bilayer (f-BL) islands (of size ~60 nm) within SA monolayer (ML), of commensurate thickness (~2.6 nm). Further compression, gradually rejects the less hydrophilic f-BL islands from the mixed layer to form EO P3HT BL islands (of coverage in-tune with starting composition) on top of SA ML. The formation of nearly covered P3HT(BL)/SA(ML) structured film on solid substrate is evident for the first time, which (even of limited P3HT thickness) has immense importance in the device properties, as the current in the bottom-gated organic thin-film transistors is known to travel only within few ML region near gate-dielectric.

Transition Metal Phthalocyanines as Redox Mediators in Li-O2 Batteries: A Combined Experimental and Theoretical Study of the Influence of 3d Electrons in Redox Mediation.

Redox mediation is an innovative strategy for ensuring efficient energy harvesting from metal-oxygen systems. This work presents a systematic exploratory analysis of first-row transition-metal phthalocyanines as solution-state redox mediators for lithium-oxygen batteries. Our findings, based on experiment and theory, convincingly demonstrate that d5 (Mn), d7 (Co), and d8 (Ni) configurations function better compared to d6 (Fe) and d9 (Cu) in redox mediation of the discharge step. The d10 configuration (Zn) and non-d analogues (Mg) do not show any redox mediation because of the inability of binding with oxygen. The solution-state discharge product, transition-metal bound Li2O2, undergoes dissociation and oxidation in the charging step of the battery, thus confirming a bifunctional redox mediation. Apart from the reaction pathways predicted based on thermodynamic considerations, density functional theory calculations also reveal interesting effects of electrochemical perturbation on the redox mediation mechanisms and the role of the transition-metal center.

Novel Imidazole Phenoxyacetic Acids as Inhibitors of USP30 for Neuroprotection Implication via the Ubiquitin-Rho-110 Fluorometric Assay: Design, Synthesis, and In Silico and Biochemical Assays.

USP30, a deubiquitinating enzyme family, forfeits the ubiquitination of E3 ligase and Parkin on the surface of mitochondria. Inhibition of USP30 results in mitophagy and cellular clearance. Herein, by understanding structural requirements, we discovered potential USP30 inhibitors from an imidazole series of ligands via a validated ubiquitin-rhodamine-110 fluorometric assay. A novel catalytic use of the Zn(l-proline)2 complex for the synthesis of tetrasubstituted imidazoles was identified. Among all compounds investigated, 3g and 3f inhibited USP30 at IC50 of 5.12 and 8.43 µM, respectively. The binding mode of compounds at the USP30 binding site was understood by a docking study and interactions with the key amino acids were identified. Compound 3g proved its neuroprotective efficacy by inhibiting apoptosis on SH-SY5Y neuroblastoma cells against dynorphin A (10 µM) treatment. Hence, the present study provides a new protocol to design and develop ligands against USP30, thereby offering a therapeutic strategy under conditions like kidney damage and neurodegenerative disorders including Parkinson's disease.

Comparison of Femoral Neck System Versus Cannulated Cancellous Screws for the Fixation of Femoral Neck Fracture in Young Adults: A Systematic Review and Meta-Analysis.

A femoral neck fracture is a very common injury in the elderly. However, its incidence is low among young adults, usually presenting as an emergency. In young adults, implant choice is one of the important factors. This systematic review aims to analyze the femoral neck system (FNS) versus cannulated cancellous (CC) screw for the fixation of femoral neck fractures in young adults through well-defined objectives. A comprehensive search from the electronic database (PubMed, Google Scholar, Web of Science, Cochrane Library) was conducted from the beginning till February 18, 2022. The data regarding study type, authors, year of publication, country, union time, Harris hip score, intraoperative blood loss, operating time, neck shortening, and hospital stay were extracted from the selected articles and analyzed using RevMan 5.4.1 software. For continuous data, e.g., healing time, intraoperative blood loss, operation time, Harris hip score, neck shortening, and hospital stay, the mean difference (MD), either weighted mean difference (WMD) or standardized mean difference (SMD), with a 95% confidence interval (CI) was recorded. A p-value less than 0.05 was taken as statistically significant. The Newcastle Ottawa scale was used for the risk of bias assessment. Six retrospective cohort studies including 427 patients were selected for the meta-analysis. There was significantly less healing time (WMD= -1.10, 95% CI: -1.73 to -0.47), shorter operation duration (WMD=7.70, 95% CI: -0.06 to 15.46), and better Harris hip score (WMD=4.79, 95% CI: 2.12-7.46) in the FNS than CC screw fixation method. However, intraoperative blood loss was significantly less in the CC screw system (WMD=21.27, 95% CI: 8.20-34.35). There was no significant difference between the two approaches in-hospital stay duration and femoral neck shortening. This can be concluded that FNS is better than CC screw fixation for treating neck of femur fractures in adults on the outcome basis of union time, less operation time, and better Harris hip score (HHS) with significant heterogeneity.

Immune Repertoire and Advancements in Nanotherapeutics for the Impediment of Severe Steroid Resistant Asthma (SSR).

Severe steroid-resistant asthma (SSR) patients do not respond to the corticosteroid therapies due to the heterogeneity, and genome-wide variations. However, there are very limited reports pertinent to the molecular signaling underlying SSR and making pharmacologists, and formulation scientists to identify the effective therapeutic targets in order to produce novel therapies using novel drug delivery systems (NDDS). We have substantially searched literature for the peer-reviewed and published reports delineating the role of glucocorticoid-altered gene expression, and the mechanisms responsible for SSR asthma, and NDDS for treating SSR asthma using public databases PubMed, National Library of Medicine (NLM), google scholar, and medline. Subsequently, we described reports underlying the SSR pathophysiology through several immunological and inflammatory phenotypes. Furthermore, various therapeutic strategies and the role of signaling pathways such as mORC1-STAT3-FGFBP1, NLRP3 inflammasomes, miR-21/PI3K/HDAC2 axis, PI3K were delineated and these can be considered as the therapeutic targets for mitigating the pathophysiology of SSR asthma. Finally, the possibility of nanomedicine-based formulation and their applications in order to enhance the long term retention of several antioxidant and anti-asthmatic drug molecules as a significant therapeutic modality against SSR asthma was described vividly.

Development of Novel Rhodanine Analogs as Anticancer Agents: Design, Synthesis, Evaluation and CoMSIA Study.

BACKGROUND: A series of novel 5-substituted benzylidene rhodanine derivatives using four different amines were designed based on our previously developed CoMSIA (Comparative molecular similarity indices analysis) model for the anticancer activity. METHODS: The designed rhodanines were synthesized via dithiocarbamate formation, cyclization and Knoevenagel condensation. The structures of the synthesized compounds were confirmed and analyzed by spectral studies. RESULTS: The synthesized rhodanines were investigated for in vitro anticancer activities and the analogs have displayed mild to significant cytotoxicity against MCF-7 breast cancer cells. The compounds with benzyloxy substitution at the fifth position of rhodanine ring (Compounds 20, 33 and 38) system showed significant cytotoxic activity against MCF-7 cells. CoMSIA, a three-dimensional quantitative structureactivity relationship (3D-QSAR) technique was accomplished to elucidate structure-activity relationships. CONCLUSION: Based on the information derived from CoMSIA contour plots, some key features for increasing the activity of compounds have been identified and used to design new anti-cancer agents. The present developed CoMSIA model displayed good external predictability, r2pred of 0.841 and good statistical robustness.

Evolution of Electronic Structures of Polar Phthalocyanine-Substrate Interfaces.

The electronic structures and core-level spectra of chlorogallium phthalocyanine (ClGaPc) molecules of different thicknesses (submonolayer to multilayer) adsorbed on a polycrystalline Au substrate and a highly oriented pyrolytic graphite (HOPG) substrate, before and after thermal annealing, were investigated using photoelectron spectroscopic techniques for better understanding the charge-transfer properties. The energy-level diagrams (ELDs) of the ClGaPc thin films are found to evolve with film thickness, substrate nature, and thermal annealing. The interfacial dipole moment in the active Au substrate and the molecular dipole moment in the inactive HOPG substrate mainly dictate the ELD. Annealed monolayer films on both the substrates seem to adopt a similar well-ordered Cl-up orientated molecular organization, which is quite interesting, as it certainly indicates a substrate-nature-independent energy minimum configuration. The strong interaction of the active Au substrate gives rise to additional charge transfer and state transfer (of Ga) as evident from the formation of a former lowest unoccupied molecular orbital (F-LUMO) level in the highest occupied molecular orbital (HOMO) region and a low binding energy peak in the Ga 2p3/2 core level. The presence of strong F-LUMO and molecular-dipole-related HOMOd levels in the predicted monolayer of well-ordered Cl-up oriented molecules on the Au and HOPG substrates, respectively, creates the optimum energy-level alignment (ELA) for both the systems, while the opposite shift of the vacuum levels in two different substrates makes the ionization potential (IP) for such a monolayer either minimum (on the Au substrate) or maximum (on the HOPG substrate), which is useful information for tuning the charge injection across the interface in organic semiconductor-based devices.

Two Rationally Identified Novel Glitazones Reversed the Behavioral Dysfunctions and Exhibited Neuroprotection Through Ameliorating Brain Cytokines and Oxy-Radicals in ICV-LPS Neuroinflammatory Rat Model.

The present study has planned to evaluate the neuroprotective activity of two novel glitazones in a neuroinflammatory rat model. Two novel glitazones were selected from an in-house virtual library of glitazones based on their docking scores against peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein and other parameters studied in in silico computational studies. Initially, an acute oral toxicity study was carried out for glitazones in rats to assess the toxicity profile and to determine the therapeutic range for neuroprotective evaluation. Prior to induction of neuroinflammation, the treatments with glitazones (G1 and G2) and standard pioglitazone were made for four consecutive days to respective groups. On the fifth day, the neuroinflammation was induced by intracerebroventricular (ICV) administration of lipopolysaccharides (LPS) (2 µg/µl) using stereotaxic apparatus. After 7 days, the rats were subjected to behavioral assessment followed by neurobiochemical evaluation and histopathological studies. The pre-treatment with glitazones at two dose levels (15 and 30 mg/kg) has significantly reversed behavioral dysfunctions. Glitazones have shown significant reduction in the levels of LPO, NO, TNF-α, and IL-1ß and also increased the levels of antioxidant enzymes such as SOD, CAT, and GSH in the brain of LPS-administered rats. The neuroprotection exhibited by two novel glitazones is comparable with standard pioglitazone. The PPAR-γ-dependent amelioration of cytokines and oxy-radicals released by novel glitazones during neuroinflammatory conditions may be attributed to the reversal of behavioral dysfunctions through preventing the degeneration of neurons in major regions of the brain.

Rational Design, Synthesis, and In Vitro Neuroprotective Evaluation of Novel Glitazones for PGC-1α Activation via PPAR-γ: a New Therapeutic Strategy for Neurodegenerative Disorders.

In the present study, two structurally diverse novel glitazones were designed and synthesized for activation of central PGC-1α signaling through stimulation of PPAR-γ receptor. The functional interaction between PGC-1α and PPAR-γ is a key interaction in the normal physiology of neuroprotective mechanism. Therefore, activation of PPAR-γ-dependent PGC-1α co-activator signaling could be an effective strategy to exhibit neuroprotection in several neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and cerebral ischemia. As part of rational design, analogs were designed manually based on principles of bioisosterism, followed by virtually screened using docking to predict the mode of interaction of compound towards the binding site and molecular dynamic simulation to observe the structural changes that occur during compound interaction with active site. The designed two glitazones (G1, G2) were synthesized and structurally analyzed. As part of evaluation, synthesized glitazones were subjected for preliminary neuroprotective evaluation in Lipopolysaccharide (LPS) intoxicated SH-SY5Y neuroblastoma cells. The results indicate that pre-treatment with synthesized glitazones have increased the percentage cell viability, protected the cell morphology, and decreased the release of pro-inflammatory cytokines (IL-1ß, TNF-α), lipid peroxide (LPO), and nitric oxide (NO) level in LPS intoxicated SH-SY5Y cells. Interestingly, among the two glitazones, G2 has shown significant neuroprotection in comparison to G1 and neuroprotective effect exerted by G2 was similar and comparable with the standard pioglitazone. Altogether, neuroprotection exhibited by this non-thiazolidione-based glitazones during neuroinflammatory conditions may be attributed to the activation of central PGC-1α signaling via PPAR-γ receptor.

Novel glitazones as PPARγ agonists: molecular design, synthesis, glucose uptake activity and 3D QSAR studies.

BACKGROUND: An alarming requirement for finding newer antidiabetic glitazones as agonists to PPARγ are on its utmost need from past few years as the side effects associated with the available drug therapy is dreadful. In this context, herein, we have made an attempt to develop some novel glitazones as PPARγ agonists, by rational and computer aided drug design approach by implementing the principles of bioisosterism. The designed glitazones are scored for similarity with the developed 3D pharmacophore model and subjected for docking studies against PPARγ proteins. Synthesized by adopting appropriate synthetic methodology and evaluated for in vitro cytotoxicity and glucose uptake assay. Illustrations about the molecular design of glitazones, synthesis, analysis, glucose uptake activity and SAR via 3D QSAR studies are reported. RESULTS: The computationally designed and synthesized ligands such as 2-(4-((substituted phenylimino)methyl)phenoxy)acetic acid derivatives were analysed by IR, 1H-NMR, 13C-NMR and MS-spectral techniques. The synthesized compounds were evaluated for their in vitro cytotoxicity and glucose uptake assay on 3T3-L1 and L6 cells. Further the activity data was used to develop 3D QSAR model to establish structure activity relationships for glucose uptake activity via CoMSIA studies. CONCLUSION: The results of pharmacophore, molecular docking study and in vitro evaluation of synthesized compounds were found to be in good correlation. Specifically, CPD03, 07, 08, 18, 19, 21 and 24 are the candidate glitazones exhibited significant glucose uptake activity. 3D-QSAR model revealed the scope for possible further modifications as part of optimisation to find potent anti-diabetic agents.