Regio- and diastereoselective synthesis of spiropyrroloquinoxaline grafted indole heterocyclic hybrids and evaluation of their anti-Mycobacterium tuberculosis activity

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel hybrid heterocycles comprising spiropyrrolidine, indenoquinoxaline and indole structural units in excellent yields, has been achieved through a one-pot multicomponent process involving 1,3-dipolar cycloaddition as a key step. The 1,3-dipolar component is the azomethine ylide generated in situ from indenoquinoxaline and l-tryptophan and reacts with various substituted β-nitrostyrenes affording the spiroheterocyclic hybrids. The ring system thus created possesses two C–C and three C–N bonds and four adjacent stereogenic carbons, one of which is quaternary and the reaction proceeded with full diastereomeric control. All the synthesized compounds were assayed for their in vitro activity against Mycobacterium tuberculosis H37Rv using MABA assay. Interestingly, the compound bearing a 2-fluoro substituent on the aryl ring displayed an equipotent activity (MIC 1.56 μg mL⁻¹) to ethambutol against Mycobacterium tuberculosis H37Rv.

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel spiropyrrolidine tethered indole hybrids in excellent yields employing a one-pot multicomponent 1,3-dipolar cycloaddition strategy.     

Highly fluorescent aryl-cyclopentadienyl ligands and their tetra-nuclear mixed metallic potassium–dysprosium clusters

Two alkyl substituted triaryl-cyclopentadienyl ligands [4,4′-(4-phenylcyclopenta-1,3-diene-1,2-diyl)bis(methylbenzene) (1) and 4,4′,4′′-(cyclopenta-1,3-diene-1,2,4-triyl)tris(methylbenzene) (2)] have been synthesized via cross-aldol condensation followed by Zn-dust mediated cyclization and acid catalyzed dehydration reactions. The fluorescence properties of 1 and 2 have been studied in solution and solid state. The ligands exhibited aggregation-induced emission enhancement (AIEE) in THF/water solution. 1 and 2 have been found to be significantly more fluorescent in the solid state than in their respective solutions. This phenomenon can be attributed to the strong intermolecular CH⋯π interactions present in 1 and 2 which leads to the tight packing of molecules in their solid-state. Both 1, 2 and their corresponding anions have been studied by theoretical calculations. Ligands 1 and 2 have been shown to react with anhydrous DyCl₃ in the presence of potassium metal at high temperature to afford two fluorescent chloride-bridged tetra-nuclear mixed potassium–dysprosium metallocenes [(Me₂Cp)₄Dy₂^IIICl₄K₂]·3.5(C₇H₈) (5) and [(Me₃Cp)₄Dy₂^IIICl₄K₂]·3(C₇H₈) (6), respectively in good yields.

Alkyl substituted triaryl-cyclopentadienyl ligands with aggregation-induced emission enhancement (AIEE) properties and their applications in the syntheses of novel chloride bridged tetra-nuclear mixed potassium–dysprosium metallocenes.     

Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies

Introduction: Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection. Given the role of microglia in neuroinflammation, recent studies have attempted to unravel the mechanisms that aid to establish microglial cell-based therapy.

Areas covered: While total suppression of microglial activation may compromise its beneficial role in tissue repair in the aftermath of an insult, the benefits of modulating microglial activation and promoting microglia polarization to a neuroprotective phenotype have been highlighted recently.

Expert opinion: So far, the therapeutic strategy focussed on neutralizing microglia-mediated neuroinflammation using drugs that block the release of pro-inflammatory mediators has limitations, such as unwarranted side effects. Recent advances reveal several alternative molecular targets and potential epi-drugs that are capable of modulating microglial function and promoting neuroprotection. This review discusses the recent progress made in understanding the mechanisms of microglia-mediated neuroinflammation in various neuropathologies, and the emerging anti-inflammatory therapeutic strategies in this field.     

Sulfated polysaccharide isolated from Ulva lactuca attenuates d-galactosamine induced DNA fragmentation and necrosis during liver damage in rats

Context: Ulva lactuca Linnaeus (Chlorophyceae), a commonly distributed seaweed, is rich in polysaccharide but has not been studied extensively.

Objective: The present study investigated the effects of crude fraction of Ulva lactuca polysaccharide (ULP) on d-galactosamine (d-Gal)-induced DNA damage, hepatic oxidative stress, and necrosis in rats.

Materials and methods: The rats were treated with ULP (100?mg/kg, orally) for 4 weeks before a single intraperitoneal injection of d-Gal (500?mg/kg). In addition to liver cell necrosis and DNA damage, antioxidant parameters, such as lipid peroxide (LPO), superoxide dismutase, and catalase, and histopathology of liver tissue were evaluated.

Results: ULP pre-treatment significantly attenuated a d-Gal-induced decrease in DNA and RNA levels (3.67?±?0.38) and (5.42?±?0.46), respectively. Comet tail length and acridine staining confirmed the number of cells undergoing necrosis were relatively lower in ULP treated rats (30?µm and 8–10% of counted cells) compared to rats treated with d-Gal (60?µm and 16% of counted cells). Biochemical (LPO, SOD and CAT) and histological evaluation (p?d-Gal-induced elevation of LPO and infiltration of inflammatory cells into liver tissue.

Discussion and conclusion: Although our previous studies have reported on the protective role of ULP against liver toxicity, our present findings show that ULP improved the hepatic antioxidant defense system against d-Gal-induced DNA damage and necrosis in rats.     

Large Molecule Run Acceptance: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

The L1 Global Harmonization Team provides recommendations specifically for run acceptance of ligand binding methods used in bioanalysis of macromolecules in support of pharmacokinetics. The team focused on standard curve calibrators and quality controls for use in both pre-study validation and in-study sample analysis, including their preparation and acceptance criteria. The team also considered standard curve editing and the concept of total error.     

β-Asarone Exhibits Antifungal Activity by Inhibiting Ergosterol Biosynthesis in Aspergillus niger ATCC 16888

Fungi play an important role in the degradation of leather goods. Economics often influence the choice of fungicide, thus, search for highly effective and low cost fungicides is immensely important. The authors have screened antifungal activity of ten Indian traditional medicinal plants viz Acalypha fruticosa, Acalypha indica, Aegle marmelos, Adathoda vasika, Calotropis gigantea, Erythrina indica, Morinda citrifolia, Nerium oleander, Pithecellobium dulce, and Acorus calamus based upon their traditional knowledge and usage. Various solvent extracts and essential oils were screened for antifungal activity against Aspergillus niger. The antifungal potency was compared to untreated control and standard antifungal drugs itraconazole and voriconazole. The bioactive principle from highly active fragment was isolated and chemically characterized. The mode of action was determined by a range of studies that include the lesion of plasma membrane, ergosterol content in the plasma membrane, acidification of external medium, and mitochondrial dehydrogenase activity in A. niger ATCC 16888. Among the ten plants studied, A. calamus exhibited greater antifungal potency in comparison to untreated control and standard drugs itraconazole and voriconazole. The minimum inhibitory concentration of both methanolic extract and essential oil of A. calamus against A. niger ATCC 16888 is around 5 µg/ml. The authors identified β-Asarone as the bioactive principle of A. calamus using spectral studies viz ultraviolet–visible spectroscopy, Fourier transform infrared spectroscopy and gas chromatography coupled mass spectroscopy. The results indicate that β-Asarone interfere and reduces the ergosterol content in the plasma membrane of A. niger ATCC 16888 thus exert their antifungal activity.