IN VITRO ANTIOXIDANT, ANTIMICROBIAL AND ADMET STUDY OF NOVEL FURAN/BENZOFURAN C-2 COUPLED QUINOLINE HYBRIDS

Objectives: Synthesis of novel 2-(benzofuran-2-yl) and 2-(furan-2-yl) quinoline-4- carboxylates and their [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol, [2-(1-furan-2-yl) quinolin-4-yl] methanol and its derivatives for antioxidant, antimicrobial and ADMET study.Methods: Synthesis was carried with conventional method and the structures were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The antioxidant activity was performed by DPPH and H2O2 radical scavenging method. Antimicrobial investigation was established by cup plate and food poison technique. The in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) study of the drug was carried out in ACD/lab-2.Results: The antioxidant activity results revealed that, compounds 4b-c, 5a-b, 10c and 10f exhibited good DPPH radical and hydrogen peroxide scavenging activity. The antibacterial results revealed that, compounds 4c, 5a-b, 10b, 10d and 10f exhibited good activity against Escherichia coli, Klebsiella pneumonia and Salmonella typhimurium. Further, the antifungal activity results showed that, compounds 4c, 5c and 10c-e were showing good activity against Aspergillus flavus and Candida neoformans.  The mean value of P<0.05 were considered to be statistically significant. The ADMET results revealed that compounds emerged as a potential candidate for antioxidant and antimicrobial agents.Conclusion: The study reveals that compounds containing furan/benzofuran coupled heterocycles are play the important role for activity as they possess potent antioxidant and antimicrobial agents. The in silico ADME analysis also suggesting the compounds were in acceptable range to obey the pharmacokinetic parameters.Â

3-(2-Bromo­acet­yl)-6-fluoro-2H-chromen-2-one

The non-H atoms of the title compound, C11H6BrFO3, are essentially coplanar (r.m.s. deviation for all non-H atoms = 0.074 Å). In the crystal, the molecules are linked by C—H⋯O and C—H⋯Br inter­actions

The Electrochemical Behaviour of Novel Multifunctional a-Hydroxymethylated Nitroalkenes at Glassy Carbon and Wax Impregnated Carbon Paste Electrodes

The electrochemical behaviour of novel multifunctional a-hydroxymethylated nitroalkenes was studied with respect to oxidation of –OH moiety and reduction of nitro group using the cyclic voltammetric technique at glassy carbon and wax impregnated carbon paste electrodes with sulphuric acid as the supporting electrolyte. The –OH moiety attached to the nitroalkene side chain was found to undergo irreversible four electrons electrochemical oxidation to form an acid at the glassy carbon electrode but no oxidation was observed at the wax impregnated carbon paste electrode. Oxidation in sulphuric acid medium becomes easier with increasing the sulphuric acid concentration. This unusual behaviour is attributed to the formation of a sixmembered cyclic structure at lower concentrations of sulphuric acid due to intramolecular hydrogen bonding. Going to the lower potential range, reduction of nitro group was observed in sulphuric acid medium both at the glassy carbon and wax impregnated carbon paste electrodes. A comparative study indicated easier reduction at the glassy carbon electrode. Non hydroxymethylated beta nitroalkenes undergo reduction at a lower negative potential compared to the corresponding a-hydroxymethylated nitroalkenes

Out FOXing Parkinson Disease: Where Development Meets Neurodegeneration

The central survival role of FOX proteins may allow a unified view of the genetic and environmental factors that cause Parkinson disease

Gli1 Is an Inducing Factor in Generating Floor Plate Progenitor Cells from Human Embryonic Stem Cells

Generation of mesencephalic dopamine (mesDA) neurons from human embryonic stem cells (hESCs) requires several stages of signaling from various extrinsic and intrinsic factors. To date, most methods incorporate exogenous treatment of Sonic hedgehog (SHH) to derive mesDA neurons. However, we and others have shown that this approach is inefficient for generating FOXA2+ cells, the precursors of mesDA neurons. As mesDA neurons are derived from the ventral floor plate (FP) regions of the embryonic neural tube, we sought to develop a system to derive FP cells from hESC. We show that forced expression of the transcription factor GLI1 in hESC at the earliest stage of neural induction, resulted in their commitment to FP lineage. The GLI1+ cells coexpressed FP markers, FOXA2 and Corin, and displayed exocrine SHH activity by ventrally patterning the surrounding neural progenitors. This system results in 63% FOXA2+ cells at the neural progenitor stage of hESC differentiation. The GLI1-transduced cells were also able to differentiate to neurons expressing tyrosine hydroxylase. This study demonstrates that GLI1 is a determinant of FP specification in hESC and describes a highly robust and efficient in vitro model system that mimics the ventral neural tube organizer. Stem Cells 2010;28:1805–181

The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age

Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine

Ectopic Wnt/Beta–Catenin Signaling Induces Neurogenesis in the Spinal Cord and Hindbrain Floor Plate

The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis

Developmental Transcriptional Networks Are Required to Maintain Neuronal Subtype Identity in the Mature Nervous System

During neurogenesis, transcription factors combinatorially specify neuronal fates and then differentiate subtype identities by inducing subtype-specific gene expression profiles. But how is neuronal subtype identity maintained in mature neurons? Modeling this question in two Drosophila neuronal subtypes (Tv1 and Tv4), we test whether the subtype transcription factor networks that direct differentiation during development are required persistently for long-term maintenance of subtype identity. By conditional transcription factor knockdown in adult Tv neurons after normal development, we find that most transcription factors within the Tv1/Tv4 subtype transcription networks are indeed required to maintain Tv1/Tv4 subtype-specific gene expression in adults. Thus, gene expression profiles are not simply “locked-in,” but must be actively maintained by persistent developmental transcription factor networks. We also examined the cross-regulatory relationships between all transcription factors that persisted in adult Tv1/Tv4 neurons. We show that certain critical cross-regulatory relationships that had existed between these transcription factors during development were no longer present in the mature adult neuron. This points to key differences between developmental and maintenance transcriptional regulatory networks in individual neurons. Together, our results provide novel insight showing that the maintenance of subtype identity is an active process underpinned by persistently active, combinatorially-acting, developmental transcription factors. These findings have implications for understanding the maintenance of all long-lived cell types and the functional degeneration of neurons in the aging brain

SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain