Design,Synthesis, Antibacterial Evaluation and Molecular Docking Studies of Some Newer Baenzothiazole Containing Aryl and Alkaryl Hydrazides

The alarming rise of bacterial resistance is occurring worldwide and endangering the efficacy of antibiotics. Therefore, development of new and efficient antibacterial agents remains paramount. In the present work, we designed and synthesized a series of N′-(1,3-benzothiazol-2-yl)-substituted aryl/aralkyl hydrazides C1 – C27 and evaluated them in vitro for their antibacterial activity. Among all tested compounds, C10 , C15 , and C24 showed potent activity against Staphylococcus aureus ATCC 43300 (MRSA). Minimum bactericidal concentration studies of synthesized compounds are performed against selected bacterial strains. Time kill kinetics showed that the compounds C10 and C15 possess bactericidal activity against MRSA ATCC 43300, while compound C24 possess bactericidal activity against S. aureus NCIM 5022. In the extra-precision docking, compounds C1 – C27 exhibited interactions mainly with the N-terminal and central domains of S. aureus GyrB catalytic pocket. Binding free energy (ΔG_bind) of compounds C1 – C27 /3U2K complexes were computed by MM-GBSA approach. Free energy components indicated Coulomb energy term as favorable for binding, while van der Waals and electrostatic solvation energy terms strongly disfavored the binding. ADMET properties of synthesized compounds C1 – C27 are also computed.     

Neurons under viral attack: Victims or warriors?

When the central nervous system (CNS) is under viral attack, defensive antiviral responses must necessarily arise from the CNS itself to rapidly and efficiently curb infections with minimal collateral damage to the sensitive, specialized and non-regenerating neural tissue. This presents a unique challenge because an intact blood–brain barrier (BBB) and lack of proper lymphatic drainage keeps the CNS virtually outside the radar of circulating immune cells that are at constant vigilance for antigens in peripheral tissues. Limited antigen presentation skills of CNS cells in comparison to peripheral tissues is because of a total lack of dendritic cells and feeble expression of major histocompatibility complex (MHC) proteins in neurons and glia. However, research over the past two decades has identified immune effector mechanisms intrinsic to the CNS for immediate tackling, attenuating and clearing of viral infections, with assistance pouring in from peripheral circulation in the form of neutralizing antibodies and cytotoxic T cells at a later stage. Specialized CNS cells, microglia and astrocytes, were regarded as sole sentinels of the brain for containing a viral onslaught but neurons held little recognition as a potential candidate for protecting itself from the proliferation and pathogenesis of neurotropic viruses. Accumulating evidence however indicates that extracellular insult causes neurons to express immune factors characteristic of lymphoid tissues. This article aims to comprehensively analyze current research on this conditional alteration in the protein expression repertoire of neurons and the role it plays in CNS innate immune response to counter viral infections.     

Design of a Non-glycosylated Outer Domain-derived HIV-1 gp120 Immunogen That Binds to CD4 and Induces Neutralizing Antibodies

The outer domain (OD) of the HIV-1 envelope glycoprotein gp120 is an important target for vaccine design as it contains a number of conserved epitopes, including a large fraction of the CD4 binding site. Attempts to design OD-based immunogens in the past have met with little success. We report the design and characterization of an Escherichia coli-expressed OD-based immunogen (OD_EC), based on the sequence of the HxBc2 strain. The OD_EC-designed immunogen lacks the variable loops V1V2 and V3 and incorporates 11 designed mutations at the interface of the inner and the outer domains of gp120. Biophysical studies showed that OD_EC is folded and protease-resistant, whereas OD_EC lacking the designed mutations is highly aggregation-prone. In contrast to previously characterized OD constructs, OD_EC bound CD4 and the broadly neutralizing antibody b12 but not the non-neutralizing antibodies b6 and F105. Upon immunization in rabbits, OD_EC was highly immunogenic, and the sera showed measurable neutralization for four subtype B and one subtype C virus including two b12-resistant viruses. In contrast, sera from rabbits immunized with gp120 did not neutralize any of the viruses. OD_EC is the first example of a gp120 fragment-based immunogen that yields significant neutralizing antibodies.     

Effect of chemical and microbial vitamin B<Subscript>12</Subscript> analogues on production of vitamin B<Subscript>12</Subscript>

Strain improvement by genetic manipulation or optimization of fermentation conditions for overproduction of vitamin B₁₂ has a drawback due to feed back inhibition. To resist the feed back inhibition by analogues of vitamin B₁₂ in Propionibacterium freudenrechii subsps. shermanii (OLP-5), we have tested with microbially separated B₁₂ analogues from three different strains. Microbial analogues were differentiated from commercially available vitamin B₁₂ by high pressure liquid chromatography and spectrophotometric method. An analogue isolated from NRRL-B-4327 was shown to increase vitamin B₁₂ concentration from 18.53 ± 0.15 to 31.67 ± 0.58 mg/l in OLP-5 strain. The presence of chemical analogue (ICH₂ Co(DH)₂ (H₂Py)₄) increased vitamin B₁₂ production from 16.13 ± 0.15 to 18.53 ± 0.15 mg/l in OLP-5. These findings revealed that addition of B₁₂ analogues in fermentation media have developed strain resistance to feed back inhibition by vitamin B₁₂.     

Hepatitis C virus NS5A binds to the mRNA cap-binding eukaryotic translation initiation 4F (eIF4F) complex and up-regulates host translation initiation machinery through eIF4E-binding protein 1 inactivation

Initiation, a major rate-limiting step of host protein translation, is a critical target in many viral infections. Chronic hepatitis C virus (HCV) infection results in hepatocellular carcinoma. Translation initiation, up-regulated in many cancers, plays a critical role in tumorigenesis. mTOR is a major regulator of host protein translation. Even though activation of PI3K-AKT-mTOR by HCV non-structural protein 5A (NS5A) is known, not much is understood about the regulation of host translation initiation by this virus. Here for the first time we show that HCV up-regulates host cap-dependent translation machinery in Huh7.5 cells through simultaneous activation of mTORC1 and eukaryotic translation initiation factor 4E (eIF4E) by NS5A. NS5A, interestingly, overexpressed and subsequently hyperphosphorylated 4EBP1. NS5A phosphorylated eIF4E through the p38 MAPK-MNK pathway. Both HCV infection and NS5A expression augmented eIF4F complex assembly, an indicator of cap-dependent translation efficiency. Global translation, however, was not altered by HCV NS5A. 4EBP1 phosphorylation, but not that of S6K1, was uniquely resistant to rapamycin in NS5A-Huh7.5 cells, indicative of an alternate phosphorylation mechanism of 4EBP1. Resistance of Ser-473, but not Thr-308, phosphorylation of AKT to PI3K inhibitors suggested an activation of mTORC2 by NS5A. NS5A associated with eIF4F complex and polysomes, suggesting its active involvement in host translation. This is the first report that implicates an HCV protein in the up-regulation of host translation initiation apparatus through concomitant regulation of multiple pathways. Because both mTORC1 activation and eIF4E phosphorylation are involved in tumorigenesis, we propose that their simultaneous activation by NS5A might contribute significantly to the development of hepatocellular carcinoma.     

Structurally unique biflavonoids from Selaginella chrysocaulos and Selaginella bryopteris

Chemical investigation of Selaginella chrysocaulos from Northeast India yielded three new (i.e., 1-3) and two known biflavonoids. From Selaginella bryopteris, collected in the southern part of India, one new (11) and eleven known biflavonoids of the amentoflavone- and hinokiflavone-type were isolated and identified. The structures of the compounds were elucidated by 1D- and 2D-NMR spectroscopy, and by mass spectrometry. The absolute configurations of chiral biflavonoids with flavanone subunits (from S. bryopteris) were determined with the aid of circular-dichroism (CD) spectroscopy. Several very rare or even unprecedented substructures in biflavonoids were found.     

Cashew nut shell oil as a potential feedstock for biodiesel production: An overview

Biodiesel outperforms diesel in emissions and engine performance. They burn efficiently in diesel engines and are eco-friendly. Since cashew nut shell liquid (CNSO) is waste, commercial biodiesel production from it should be profitable. CNSO is cheap and can reduce cashew processing factory waste. From cashew kernels, CNSL is extracted using various mechanical, thermal, and solvent extraction techniques. This article examines current research into using cashew nutshell liquid biodiesel (CNSLBD) in diesel engines. The work also discusses Indian biodiesel demand, availability, export information, life cycle cost analysis, cost economics of per hectare yield, Indian government initiative of CNSO. This review also evaluates the viability of this fuel as an alternative energy source. CNSLBD is a prospective alternative fuel that has the potential to benefit both the cashew nut industry and the energy industry. In addition to this, the study examines the procedures for extracting CNSO. According to the findings of the study, CNSO is a prospective alternative fuel that has the potential to benefit both the cashew nut industry and the energy industry.     

Structural elucidation,theoretical investigation,biological screening and molecular docking studies of metal(II) complexes of NN donor ligand derived from 4-(2-aminopyridin-3-methylene)aminobenzoic acid

Complexes of 4-(((2-aminopyridin-3-yl)methylene)amino)benzoic acid ligand with cobalt(II) (1), nickel(II) (2), copper(II) (3), zinc(II) (4) and palladium(II) (5) are synthesized and characterized by using different spectroscopic methods like, UV–Visible, infrared, ¹H, ¹³C NMR, molar conductance, ESR and elemental analysis. Quantum chemical computations were made using DFT (density functional theory), B3LYP functional and 6-31+?+G(d,p)/SDD basis set in order to determine optimized structure parameters, frontier molecular orbital parameters and NLO properties. Based on DFT and experimental evidence, the complexes ensured that the octahedral geometry have been proposed for complexes 1, 2 and 4, square planar for complexes 3 and 5. All the complexes showed only residual molar conductance values and hence they were considered as non-electrolytes in DMF. In addition, the anti-proliferative activity of the compounds was evaluated against different human cancer cell lines (IMR-32, MCF-7, COLO205, A549, HeLa and HEK 293) and cisplatin is used as a reference drug. Compounds 1 and 4 showed remarkable cytotoxicity in five cancer cell lines tested except MCF-7. Also, the compounds were examined for their in vitro antimicrobial and scavenging activities. The molecular docking results are well corroborated with the experimental anticancer activity results.

     

Nucleolar binding sequences of the ribosomal protein S6e family reside in evolutionary highly conserved peptide clusters

Proteomic analyses of the nucleolus have revealed almost 700 functionally diverse proteins implicated in ribosome biogenesis, nucleolar assembly, and regulation of vital cellular processes. However, this nucleolar inventory has not unveiled a specific consensus motif necessary for nucleolar binding. The ribosomal protein family characterized by their basic nature should exhibit distinct binding sequences that enable interactions with the rRNA precursor molecules facilitating subunit assembly. We succeeded in delineating 2 minimal nucleolar binding sequences of human ribosomal protein S6 by fusing S6 cDNA fragments to the 5' end of the LacZ gene and subsequently detecting the intracellular localization of the beta-galactosidase fusion proteins. Nobis1 (nucleolar binding sequence 1), comprising of 4 highly conserved amino acid clusters separated by glycine or proline, functions independently of the 3 authentic nuclear localization signals (NLSs). Nobis2 consists of 2 conserved peptide clusters and requires the authentic NLS2 in its native context. Similarly, we deduced from previous publications that the single Nobis of ribosomal protein S25 is also highly conserved. The functional protein domain organization of the ribosomal protein S6e family consists of 3 modules: NLS, Nobis, and the C-terminal serine cluster of the phosphorylation sites. This modular structure is evolutionary conserved in vertebrates, invertebrates, and fungi. Remarkably, nucleolar binding sequences of small and large ribosomal proteins reside in peptide clusters conserved over millions of years.