Effect of sulfonamide derivatives of phenylglycine on scopolamine-induced amnesia in rats.

Alzheimer's disease is a neurodegenerative disease responsible for dementia and other neuropsychiatric symptoms. In the present study, compounds 30 and 33, developed earlier in our laboratory as selective butyrylcholinesterase inhibitors, were tested against scopolamine-induced amnesia to evaluate their pharmacodynamic effect. The efficacy of the compounds was determined by behavioral experiments using the Y-maze and the Barnes maze and neurochemical testing. Both compounds reduced the effect of scopolamine treatment in the behavioral tasks at a dose of 20 mg/kg. The results of the neurochemical experiment indicated a reduction in cholinesterase activity in the prefrontal cortex and the hippocampus. The levels of antioxidant enzymes superoxide dismutase and catalase were restored compared to the scopolamine-treated groups. The docking study on rat butyrylcholinesterase (BChE) indicated tight binding, with free energies of -9.66 and -10.23 kcal/mol for compounds 30 and 33, respectively. The two aromatic amide derivatives of 2-phenyl-2-(phenylsulfonamido) acetic acid produced stable complexes with rat BChE in the molecular dynamics investigation.

Cardiac synovial sarcoma masquerading as effusive constrictive pericarditis.

Primary cardiac synovial sarcoma is a rare entity, arising from the pericardium or the chambers of the heart. It presents in the 4th decade of life with a striking male predisposition. We describe an unusual case of a 22-year-old female who presented with complaints of dyspnoea on exertion, palpitations, and chest pain. Trans-thoracic echocardiography was suggestive of a cystic pericardial mass with pericardial effusion anterior and lateral to the right ventricle. Computed tomography scan (CT scan) revealed thick-walled predominantly cystic lesion over the left ventricle with gross pericardial effusion with internal septations. These findings were suggestive of an infected pericardial cyst. Upon surgery, an adherent mass in the pericardial cavity was found which was not separable from the right heart structures, the great vessels, and the left ventricle. Biopsy was taken, histopathology was suggestive of spindle cell neoplasm, and an immunohistochemistry analysis revealed Transducin-like enhancer of split 1 (TLE 1)-positive malignant spindle cell tumour likely synovial sarcoma. After surgery, the patient received serial adjuvant chemo-radiation therapy. The synovial sarcoma masqueraded as effusive constrictive pericarditis, due to which it eluded preoperative diagnosis.

Discovery of reversible selective monoamine oxidase B inhibitors with anti-acetylcholinesterase activity derived from 4-oxo-N-4-diphenyl butanamides.

Aim: Multitargeted drugs are essential for the treatment of various neurodegenerative disorders, because of their complex nature. This study aimed to develop novel small molecules as selective monoamine oxidase B (MAO-B) inhibitors with cholinesterase inhibition. Materials & methods: With the help of fragment-based drug design, some 4-oxo-N-4-diphenyl butanamides were designed and synthesized as MAO-B inhibitors with anti-acetylcholinesterase (AChE) activity. Results: Compound 6m showed the best neuroprotection, with reversible selective MAO-B inhibition activity (IC50 = 11.54 ± 0.64 nM). Compounds 6b, 6h, 6j, 6n and 6p (IC50 = 20.90 ± 0.50, 17.25 ± 0.90, 15.85 ± 0.16, 16.81 ± 0.85 and 25.19 ± 0.17 nM, respectively) also appeared as potent and selective MAO-B inhibitors with anti-AChE activity. Conclusion: The present study suggests potent, neuroprotective and nontoxic lead compounds as selective MAO-B inhibitors with anti-AChE activity.

Genetic analysis for detection of genes associated to drought tolerance in rice accessions belonging to north east India.

INTRODUCTION: The North East (NE) India is rich in biodiversity and also considered as the secondary centre for origin of rice. The NE rice accessions was characterized previously using genetic markers and morphological traits. Simultaneously, genome-wide association studies (GWAS) reveal significant marker-trait associations for the drought tolerance traits. METHODS AND RESULTS: The genetic diversity and population structure of 296 NE rice accessions were studied using 96,712 single nucleotide polymorphism (SNP) markers distributed across 12 chromosomes. The accessions were clustered into two major sub-groups (SG). A total of 91 accessions were assembled as SG1 and 114 accessions as SG2, while the remaining 91 were admixture genotypes. A total of 200 genotypes belonging to different groups were phenotyped for yield component traits under drought and control conditions. The GWAS was performed to identify significant marker-trait associations (MTAs). Consequently, 47 MTAs were detected under drought, exhibiting 0.02-9.95% of phenotypic variance (P.V.). Whereas 58 MTAs were discovered under control conditions, showing a 0.01-9.74% contribution to the phenotype. Through in-silico mining of QTLs, 2999 genes were identified. Among these; only 22 genes were directly associated with stress response. CONCLUSION: These QTLs/genes may be deployed for marker-assisted pyramiding to improve drought tolerance in popular drought susceptible rice varieties.

Understanding the salinity stress on plant and developing sustainable management strategies mediated salt-tolerant plant growth-promoting rhizobacteria and CRISPR/Cas9.

Soil salinity is a worldwide concern that decreases plant growth performance in agricultural fields and contributes to food scarcity. Salt stressors have adverse impacts on the plant's ionic, osmotic, and oxidative balance, as well as numerous physiological functions. Plants have a variety of coping strategies to deal with salt stress, including osmosensing, osmoregulation, ion-homeostasis, increased antioxidant synthesis, and so on. Not only does salt stress cause oxidative stress but also many types of stress do as well, thus plants have an effective antioxidant system to battle the negative effects of excessive reactive oxygen species produced as a result of stress. Rising salinity in the agricultural field affects crop productivity and plant development considerably; nevertheless, plants have a well-known copying mechanism that shields them from salt stress by facilitated production of secondary metabolites, antioxidants, ionhomeostasis, ABAbiosynthesis, and so on. To address this problem, various environment-friendly solutions such as salt-tolerant plant growth-promoting rhizobacteria, eco-friendly additives, and foliar applications of osmoprotectants/antioxidants are urgently needed. CRISPR/Cas9, a new genetic scissor, has recently been discovered to be an efficient approach for reducing salt stress in plants growing in saline soil. Understanding the processes underlying these physiological and biochemical responses to salt stress might lead to more effective crop yield control measures in the future. In order to address this information, the current review discusses recent advances in plant stress mechanisms against salinity stress-mediated antioxidant systems, as well as the development of appropriate long-term strategies for plant growth mediated by CRISPR/Cas9 techniques under salinity stress.

Combined ligand-based and structure-based design of PDE 9A inhibitors against Alzheimer's disease.

PDE9 enzyme hydrolyzes cGMP, which is involved in the regulation of synaptic plasticity through the NMDA pathway (a well-known excitotoxic target for AD) via activation of calcium/calmodulin-dependent neuronal NO synthases in the postsynaptic neurons. The inhibition of PDE9 leads to elevated cGMP levels, causing enhanced NMDA signaling and thus contributing to an increase in synaptic plasticity and stabilization. Therefore, it could be considered a pertinent target for AD drug discovery. PF-04447943 and BI-409306 targeting PDE9 are undergoing clinical trials (Phase II). The present study encompasses a pharmacophoric approach to identify potent PDE9 inhibitors using various computational methods. Pharmacophores generated from the PDB 6A3N yielded 37,554 virtual hits, which underwent drug likeliness and PAINS filtering to arrive at a few virtual leads. The leads were further subjected to extra precision docking, ADMET predictions, and molecular dynamics. The final hits, ZINC000001305675 and ZINC000000377099, showed superior docking scores of - 10.90 and - 10.30 kcal/mol and satisfactory predicted ADMET scores. The hits were subjected to molecular dynamics (MD) studies, wherein they formed stable complexes with PDE9 protein and had ligand RMSDs within acceptable limits. The processes involved in the combined ligand and structure-based strategies.

Near-Infrared Fluorescent Probes as Imaging and Theranostic Modalities for Amyloid-Beta and Tau Aggregates in Alzheimer's Disease.

A person suspected of having Alzheimer's disease (AD) is clinically diagnosed for the presence of principal biomarkers, especially misfolded amyloid-beta (Aß) and tau proteins in the brain regions. Existing radiotracer diagnostic tools, such as PET imaging, are expensive and have limited availability for primary patient screening and pre-clinical animal studies. To change the status quo, small-molecular near-infrared (NIR) probes have been rapidly developed, which may serve as an inexpensive, handy imaging tool to comprehend the dynamics of pathogenic progression in AD and assess therapeutic efficacy in vivo. This Perspective summarizes the biochemistry of Aß and tau proteins and then focuses on structurally diverse NIR probes with coverages of their spectroscopic properties, binding affinity toward Aß and tau species, and theranostic effectiveness. With the summarized information and perspective discussions, we hope that this paper may serve as a guiding tool for designing novel in vivo imaging fluoroprobes with theranostic capabilities in the future.

Rational approaches of drug design for the development of selective estrogen receptor modulators (SERMs), implicated in breast cancer.

Drug discovery and development have gained momentum due to the rational drug design by engaging computational tools and bioinformatics methodologies. Bioisosteric replacements and hybrid molecular approaches are the other inventive processes, used by medicinal chemists for the desired modifications of leads for clinical drug candidates. SERMs, ought to produce inhibitory activity in breast, uterus and agonist activity in other tissues, are beneficial for estrogen-like actions. ER subtypes α and ß are hormone dependent modulators of intracellular signaling and gene expression, and development of ER selective ligands could be an effective approach for treatment of breast cancer. This report has critically investigated the possible designing considerations of SERMs, their in silico interactions, and potent pharmacophore generation approaches viz. indole, restricted benzothiophene [3, 2-b] indole, carborane, xanthendione, combretastatin A-4, organometallic heterocycles, OBHS-SAHA hybrids, benzopyranones, tetrahydroisoquinolines, Dig G derivatives and their specifications in drug design and development, to rationally improve the understanding in drug discovery. This also includes various strategies for the development of dual inhibitors for the management of antiestrogenic resistance.

Multifunctional hybrid sulfonamides as novel therapeutic agents for Alzheimer's disease.

Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer's disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC50: 18.24 ± 1.62 nM), AChE (IC50: 4.28 ± 0.15 µM) and BuChE (IC50: 1.32 ± 0.02 µM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aß aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer's disease.

Estrogen signaling: An emanating therapeutic target for breast cancer treatment.

Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERß, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17ß-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.

Protein-Protein Interactions and Aggregation Inhibitors in Alzheimer's Disease.

BACKGROUND: Alzheimer's Disease (AD), a multifaceted disorder, involves complex pathophysiology and plethora of protein-protein interactions. Thus such interactions can be exploited to develop anti-AD drugs. OBJECTIVE: The interaction of dynamin-related protein 1, cellular prion protein, phosphoprotein phosphatase 2A and Mint 2 with amyloid ß, etc., studied recently, may have critical role in progression of the disease. Our objective has been to review such studies and their implications in design and development of drugs against the Alzheimer's disease. METHODS: Such studies have been reviewed and critically assessed. RESULTS: Review has led to show how such studies are useful to develop anti-AD drugs. CONCLUSION: There are several PPIs which are current topics of research including Drp1, Aß interactions with various targets including PrPC, Fyn kinase, NMDAR and mGluR5 and interaction of Mint2 with PDZ domain, etc., and thus have potential role in neurodegeneration and AD. Finally, the multi-targeted approach in AD may be fruitful and opens a new vista for identification and targeting of PPIs in various cellular pathways to find a cure for the disease.

Naphthalene, a versatile platform in medicinal chemistry: Sky-high perspective.

Naphthalene, a cytotoxic moiety, is an extensively explored aromatic conjugated system with applications in various pathophysiological conditions viz. anticancer, antimicrobial, anti-inflammatory, antiviral, antitubercular, antihypertensive, antidiabetic, anti-neurodegenerative, antipsychotic, anticonvulsant, antidepressant. Naphthalene epoxides and naphthoquinones are most reactive metabolites of naphthalene and are responsible for the covalent interaction with cysteine amino acid of cellular proteins for cytotoxic nature. Many naphthalene derived bioactive phytoconstituents are present in nature including podophyllotoxins (Etoposide, teniposide), bis-ANS 82, Rifampicin, Justiprocumin A, B, Patentiflorin A. The naphthalene-based molecules, viz. Naphyrone, tolnaftate, naftifine, nafcillin, terbinafine, propranolol, nabumetone, nafimidone, naproxen, duloxetine, lasofoxifene, bedaquiline etc. have also been approved by FDA and are being marketed as therapeutics. Thus, the naphthalene scaffold emerges as an important building block in drug discovery owing to its broad spectrum of biological activities through varying structural modifications. This review incorporates the pharmacological aspects of different types of chemically modified naphthalene-based molecules along with their activity profile. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.

Identification of selective MMP-9 inhibitors through multiple e-pharmacophore, ligand-based pharmacophore, molecular docking, and density functional theory approaches.

Matrix metalloproteinase-9 (MMP-9) is a significant target for the development of drugs for the treatment of arthritis, CNS disorders, and cancer metastasis. The structure-based and ligand-based methods were used for the virtual screening (VS) of database compounds to obtain potent and selective MMP-9 inhibitors. Experimentally known MMP-9 inhibitors were used to grow up ligand-based three pharmacophore models utilizing Schrodinger suite. The X-ray crystallographic structures of MMP-9 with different inhibitors were used to develop five energy-optimized structure-based (e-pharmacophore) models. All developed pharmacophores were validated and applied to screen the Zinc database. Pharmacophore matched compounds were subjected to molecular docking to retrieve hits with novel scaffolds. The molecules with diverse structures, high docking scores and low binding energies for various crystal structures of MMP-9, were selected as final hits. The Induced fit docking (IFD) analysis provided significant information about the driving of inhibitor to approve a suitable bioactive conformational position in the active site of protein. Since charge transfer reaction occurs during receptor-ligand interaction, therefore, electronic features of hits (ligands) are interesting parameters to explain the binding interactions. Density functional theory (DFT) at B3LYP/6-31G* level was utilized to explore electronic features of hits. The docking study of hits using AutoDock was helpful to establish the binding interactions. The study illustrates that the combined pharmacophore approach is advantageous to identify diverse hits which have better binding affinity to the active site of the enzyme for all possible bioactive conformations. The approach used in the study is worthy to design drugs for other targets.

Physicochemical and nutritional properties of extrudates from food grade distiller's dried grains, garbanzo flour, and corn grits.

Distiller's dried grains and garbanzo flour were blended with corn grits for the development of extruded snacks using a single screw extruder. Distiller's dried grains were processed for food application and termed as food grade distiller's dried grains or FDDG. Effects of different level of FDDG addition (0%-20%) and extrusion process parameters such as barrel and die temperature (100-140°C), screw speed (100-200 rpm), and feed moisture content (14%-20% wet basis) on the physical properties (expansion ratio, bulk density, color parameters), functional properties (water absorption and solubility indices), and nutritional properties (total dietary fiber, soluble and insoluble dietary fiber and protein content) of the extrudates were investigated and optimized using response surface methodology. FDDG incorporation had a significant effect (p < 0.05) on the total dietary fiber, color parameters, water solubility, and water absorption indices of the extruded snacks. Desirable expanded extrudates with a high level of total dietary fiber and protein were obtained with blends containing 20% FDDG extruded at 140°C extrusion temperature, 167 rpm screw speed, and 19% feed moisture content. Results indicate garbanzo flour, and FDDG can be successfully blended with corn grits to produce nutritious gluten-free extruded snacks which are high in protein and dietary fiber.

Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease.

Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50 = 32.45 ±â€¯0.044, 28.65 ±â€¯0.029, BuChE, IC50 = 157.95 ±â€¯0.264, 160.58 ±â€¯0.082 and MMP-2, IC50 = 36.83 ±â€¯0.015, 19.57 ±â€¯0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Ki = 7 nM and competitive inhibition of MMP-2 with Ki = 20 nM. Compounds 52 and 46 inhibited AChE-induced Aß aggregation at 20 µM. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65 cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5 mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46.

Water mediated dielectric polarizability and electron charge transport properties of high resistance natural fibers.

Recent studies showed that silk and human hair fibers develop thermoelectric properties at optimal water, temperature and light conditions. The nature of charge carriers and the role of water in mediating charge conduction in these fibers is an unexplored issue. By studying four different classes of natural fibers, viz., silk cocoon, human hair, jute and corn silk, we uncover their common electrical transport properties and its dependence on water concentration and temperature. All these fibers uniformly exhibit nonlinear, hysteretic current - voltage characteristics, which scale with water concentration. The optimal electrical conductivity shows thermally activated hopping transport mechanism. Scanning tunneling microscope (STM) and dielectric measurements of silk cocoon fibers showed the electronic density of states and dielectric properties of the hydrated medium enhances with water concentration. Electron paramagnetic resonance (EPR) study reveals that the charge carriers in these membranes are electronic in nature. Our results are explained through the mechanism of hopping of a Polaron, which is an electron surrounded by positive charge fluctuations created by water molecules. The mechanism unravels the peculiar role water plays in mediating electrical activity in these membranes and also opens the possibility for exploring such charge transport mechanism in other biological membranes.

α-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a multifactorial progressive neurological disorder. Pathological hallmarks of PD are characterized by the presence of α-synuclein (αSyn) aggregates known as Lewy bodies. αSyn aggregation is one of the leading causes for the neuronal dysfunction and death in PD. It is also associated with neurotransmitter and calcium release. Current therapies of PD are limited to only symptomatic relief without addressing the underlying pathogenic factors of the disease process such as aggregation of αSyn. Consequently, the progression of the disease continues with the current therapies. Therefore, the modulation of αSyn aggregation is an emerging approach as a novel therapeutic target to treat PD. There are two major aspects that might be targeted therapeutically: first, protein is prone to aggregation, therefore, anti-aggregative or compounds that can break the pre-existing aggregates should be helpful. Second, there are number of molecular events that may be targeted to combat the disease.

Harvesting electricity from human hair.

Electrical conductivity of human hair is a debatable issue among hair experts and scientists. There are unsubstantiated claims that hair conducts electricity. However, hair experts provided ample evidence that hair is an insulator. Although wet hair exhibited drastic reduction in resistivity; scientists regarded hair as a proton semiconductor at the best. Here, we demonstrate that hair filaments generate electricity on absorbing water vapor between 50 degrees and 80 degrees C. This electricity can operate low power electronic systems. Essentially, we are exposing the hydrated hair polymer to a high temperature (50 degrees-80 degrees C). It has long been speculated that when certain biopolymers are simultaneously hydrated and exposed to high temperature, they exhibit significant proton hopping at a specific temperature regime. This happens due to rapid movement of water molecules on the polymer surface. This lead us to speculate that the observed flow of current is partly ionic and partly due to "proton hopping" in the hydrated nano spaces of hair filament. Such proton hopping is exceptionally high when the hydrated hair polymer is exposed to a temperature between 50 degrees and 80 degrees C. Differential scanning calorimetry data further corroborated the results and indicated that indeed at this temperature range, there is an enormous movement of water molecules on the hair polymer surface. This enormously rapid movement of water molecules lead to the "making and breaking" of innumerable hydrogen bonds and thus resulting in hopping of the protons. What is challenging is "how to tap these hopping protons to obtain useful electricity?" We achieved this by placing a bundle of hair between two different electrodes having different electro negativities, and exposing it to water vapor (water + heat). The two different electrodes offered directionality to the hopping protons and the existing ions and thus resulting in the generation of useful current. Further, by continuously hydrating the polymer with water vapor, we prolonged the process. If this interesting aspect of polymer is exploited further and fine tuned, then it will open new avenues for development of sophisticated polymer-based systems, which could be used to harvest electricity from waste heat.

Benzothiazole derivatives bearing amide moiety: potential cytotoxic and apoptosis-inducing agents against cervical cancer.

Cervical cancer is a major cause of morbidity and mortality in women worldwide. In recent years, benzothiazole analogues have attracted considerable attention in anticancer research. Therefore, in this study, the earlier reported amide series of benzothiazole derivatives were investigated for their antiproliferative activity. The activity of amide derivatives was evaluated using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometric analysis, apoptosis assay, and DNA fragmentation on two human cervical cancer cell lines: SiHa and C33-A. The data reported from this investigation indicated that benzothiazole derivatives show pronounced cytotoxicity in the HPV16-positive SiHa cells compared with HPV-negative C-33A cells. The in-vitro cytotoxicity of the compounds on the HEK-293 noncancer cell line was evaluated to establish selectivity. Cells treated with benzothiazole derivatives showed prominent morphological features as evidenced by cell shrinkage, membrane blebbing, apoptotic nuclei, and DNA fragmentation. The benzothiazole derivatives show accumulation of cells in the sub-G1 and S-phase of the cell cycle in SiHa and C33-A, respectively. In addition, these derivatives exert their beneficial effect by inducing apoptosis, in the chemoprevention of cervical cancer cells, and were further ascertained using a DNA fragmentation assay. The compounds studied showed potent cytotoxic and apoptotic properties against SiHa and C33-A cancer cell lines and thus represent an excellent starting point for further optimization of therapeutically effective anticancer drugs.