Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro α-glucosidase inhibition, and computational studies.

BACKGROUND: A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. METHODS: The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. RESULTS: All new derivatives 11a-o (IC50 values = 6.31 ± 0.03-49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. CONCLUSION: According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Nano-Graphene Oxide-supported APTES-Spermine, as Gene Delivery System, for Transfection of pEGFP-p53 into Breast Cancer Cell Lines.

PURPOSE: Genetic diseases can be the result of genetic dysfunctions that happen due to some inhibitory and/or environmental risk factors, which are mostly called mutations. One of the most promising treatments for these diseases is correcting the faulty gene. Gene delivery systems are an important issue in improving the gene therapy efficiency. Therefore, the main purpose of this study was modifying graphene oxide nanoparticles by spermine in order to optimize the gene delivery system. METHODS: Graphene oxide/APTES was modified by spermine (GOAS) and characterized by FT-IR, DLS, SEM and AFM techniques. Then pEGFP-p53 was loaded on GOAS, transfected into cells and evaluated by fluorescent microscopy and gene expression techniques. RESULTS: FT-IR data approved the GOAS sheet formation. Ninety percent of the particles were less than 56 nm based on DLS analysis. SEM analysis indicated that the sheets were dispersed with no aggregation. AFM results confirmed the dispersed structures with thickness of 1.25±0.87 nm. STA analysis showed that GOAS started to decompose from 400°C and was very unstable during the heating process. The first weight loss up to 200°C was due to the evaporation of absorbed water, the second one observed in the range of 200-550°C was assigned to the decomposition of labile oxygen- and nitrogen-containing functional groups, and the third one above 550°C was attributed to the removal of oxygen functionalities. In vitro release of DNA demonstrated the efficient activity of the new synthesized system. Ninety percent of the cells were transfected and showed the GFP under fluorescence microscopy, and TP53 gene was expressed 51-fold in BT-20 cells compared to ß-actin as the reference gene. Flow cytometry analysis confirmed the apoptosis of the cells rather than necrosis. CONCLUSION: It could be concluded that the new synthesized structure could transfer a high amount of the therapeutic agent into cells with best activity.

Nickel Ferrite (NiFe2O4) Nanoparticles as Magnetically Recyclable Nanocatalyst for Highly Efficient Synthesis of 4H-Chromene Derivatives.

An adapted one-pot route to nanocatalyst-assisted synthesis of 4H-chromenes via three component condensation reaction between dimedone, malononitrile, and a broad range of aryl aldehydes by the use of magnetic nickel ferrite nanoparticles is described. By this achievement, not only a novel route to highly efficient synthesis of these series of heterocycles was introduced but also the scope of these medicinally important products was developed via preparation of some novel products. Above all, a new application of nickel ferrite nanoparticles (NiFe2O4 NPs) as highly efficient, green and magnetically recyclable catalyst has been introduced. Overall, obtaining good to excellent yields of products, environmentally and economic benign procedure, easy handling, availability of starting materials, use of non-toxic solvents, and high recyclability of nano-catalyst could be countered as most important advantages of this methodology.

Synthesis, in vitro cytotoxicity and apoptosis inducing study of 2-aryl-3-nitro-2H-chromene derivatives as potent anti-breast cancer agents.

A series of 2-aryl-3-nitro-2H-chromenes 4a-u were designed as hybrid analogs of flavanone, ß-nitrostyrene and nitrovinylstilbene scaffolds. They were synthesized from the reaction of appropriate ß-nitrostyrenes and salicylaldehydes in good yields. In vitro cytotoxic activities of compounds 4a-u were tested against breast cancer cell lines including MCF-7, T-47D and MDA-MB-231. Most compounds exhibited good cytotoxic activity against selected cell lines, being more potent than standard drug etoposide. Representatively, 8-methoxy-3-nitro-2-(4-chlorophenyl)-2H-chromene (4l) with IC50 = 0.2 µM against MCF-7 cells, was 36-times more potent than etoposide. Apoptosis as a mechanism of cell death for selected compounds 4h and 4l was confirmed morphologically by acridine orange/ethidium bromide double staining and TUNEL analysis, as well as caspase-3 activation assay.