A potential delivery system has to be fabricated for crossing the blood-brain barrier (BBB) to reach the brain fluid for effective delivery of drugs for any neurological disorders. The present study is aimed for the delivery of donepezil through functionalized PNIPAM nanogel by overcoming the BBB using zebrafish model. We had synthesized the poly N-isopropyl acrylamide nanogels with 20 nm size for sustained drug release. The entrapment of donepezil in the nanogel was quantified as 87.5% by HPLC and its sustained drug release pattern was achieved at 37 8C using Janus green dye release assay. Acetylcholineesterase inhibition assay for the donepezil conjugated nanogel (DCN) has confirmed thermoresponsive drug release by obtaining the donepezil peak at 9.3 min retention time in HPLC. Swim behavior and heart beat rates were found to be biocompatible for the functionalized nanogel DCN in zebrafish. Histological analysis revealed increased pial surface in anterior telenchepalon region of zebrafish brain for the DCN administered fishes. DCN treated embryos exhibited minor developmental deformities above 5 mg/ml and thus confirmed its minimal toxicity and its therapeutic efficiency. This study may shed light on the development of neurospecific nanogel for targeted and sustained drug release to brain by crossing the blood-brain barrier.
18 19 Bioassay guided screening of antibacterial compounds from the cultured marine Streptomyces sp. ICN19 provided Ala-geninthiocin (1), along with its known analogs geninthiocin (2) and Valgeninthiocin (3) and the indolocarbazole staurosporine (4). The structure of 1 was determined on the basis of 1D and 2D NMR spectra and ESI-HRMS. The absolute configurations of the amino acid residues were determined by enantioselective GC-MS analysis. Compound 1 exhibited potent activity against Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, Mycobacterium smegmatis and Micrococcus luteus as well as cytotoxicity against A549 human lung carcinoma cells with an IC 50 value of 6 nM. The desirable biological activity of thiopeptides has stimulated renewed interest in the search for new antibiotics to find promising lead molecules. New groups of actinomycetes from unexplored habitats are pursued as sources of novel bioactive secondary metabolites. It is perhaps not surprising that marine Streptomyces are proving to be such a valuable source of new bioactive compounds. 1-3 As part of our continuing efforts to explore marine derived actinomycetes, a new thiopeptide antibiotic was isolated from Streptomyces strain ICN19 derived from a marine sediment. The bioassay-guided chromatographic purification yielded a new compound named as Ala-geninthiocin (1) besides the known geninthiocin (2), its analog Val-geninthiocin (3) and staurosporine (4) (Figure 1). Details of the extraction, purification, structure elucidation and biological activity are described herein. Strong activity was found by bioassay screening against Staphylococcus aureus and Candida albicans in the acetone extract of Streptomyces sp. ICN19. After extracting the active metabolites with ethyl acetate and removing the lipids with n-heptane, the residue of the extract was fractionated using a reversed phased Medium-pressure liquid chromatography (MPLC) column with a methanol/water gradient. Of the 11 fractions collected, 3 fractions (fr. 4, 6 and 7) exhibited antibacterial activity, i.e. fr. 4 and 7 were active against S. aureus and fr. 6 was active against C. albicans. Fr. 4 was further purified using preparative RP-HPLC to give Ala
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