Microwave-assisted synthesis and antitumor evaluation of a new series of thiazolylcoumarin derivatives

A new series of thiazolylcoumarin derivatives was synthesized. The designed strategy embraced a molecular hybridization approach which involves the combination of the thiazole and coumarin pharmacophores together. The new hybrid compounds were tested for in vitro antitumor efficacy over cervical (Hela) and kidney fibroblast (COS-7) cancer cells. Compounds 5f, 5h, 5m and 5r displayed promising efficacy toward Hela cell line. In addition, 5h and 5r were found to be the most active candidates toward COS-7 cell line. The four active analogs, 5f, 5h, 5m and 5r were screened for in vivo antitumor activity over EAC cells in mice, as well as in vitro cytotoxicity toward W138 normal cells. Results illustrated that 5r has the highest in vivo activity, and that the four analogs are less cytotoxic than 5-FU toward W138 normal cells. In this study, 3D pharmacophore analysis was performed to investigate the matching pharmacophoric features of the synthesized compounds with trichostatin A. In silico studies showed that the investigated compounds meet the optimal needs for good oral absorption with no expected toxicity hazards

Multitarget Therapeutics for Neurodegenerative Diseases.

No abstract availabl

Expanding the Toolbox for Label-Free Enzyme Assays: A Dinuclear Platinum(II) Complex/DNA Ensemble with Switchable Near-IR Emission

Switchable luminescent bioprobes whose emission can be turned on as a function of specific enzymatic activity are emerging as important tools in chemical biology. We report a promising platform for the development of label-free and continuous enzymatic assays in high-throughput mode based on the reversible solvent-induced self-assembly of a neutral dinuclear Pt(II) complex. To demonstrate the utility of this strategy, the switchable luminescence of a dinuclear Pt(II) complex was utilized in developing an experimentally simple, fast (10 min), low cost, and label-free turn-on luminescence assay for the endonuclease enzyme DNAse I. The complex displays a near-IR (NIR) aggregation-induced emission at 785 nm in aqueous solution that is completely quenched upon binding to G-quadruplex DNA from the human c-myc oncogene. Luminescence is restored upon DNA degradation elicited by exposure to DNAse I. Correlation between near-IR luminescence intensity and DNAse I concentration in human serum samples allows for fast and label-free detection of DNAse I down to 0.002 U/mL. The Pt(II) complex/DNA assembly is also effective for identification of DNAse I inhibitors, and assays can be performed in multiwell plates compatible with high-throughput screening. The combination of sensitivity, speed, convenience, and cost render this method superior to all other reported luminescence-based DNAse I assays. The versatile response of the Pt(II) complex to DNA structures promises broad potential applications in developing real-time and label-free assays for other nucleases as well as enzymes that regulate DNA topology

Salts and Co-Crystalline Assemblies of Tetra(4-Pyridyl)Ethylene with Di-Carboxylic Acids

Tetraarylethylene derivatives are emerging as an increasingly important family of supramolecular building blocks in both solution phase and the solid state. The utility of tetraarylethylenes stems from appealing structural features (rigidity and symmetry) and their propensity to exhibit aggregation induced emission (AIE). In an effort to investigate the luminescent sensing ability of heteroaromatic tetraarylethylenes, we previously prepared tetra(4-pyridyl)ethylene and characterized its solution phase AIE properties. We here report the successful incorporation of tetra(4-pyridyl)ethylene into three distinct salts and co-crystalline assemblies with three organic di-carboxylic acids (oxalic acid, malonic acid, and fumaric acid). Interactions between the tetra(pyridyl)ethylene and di-acid components were found to vary from conventional to charge-assisted hydrogen bonding according to the extent of proton transfer between the acid and pyridine groups. Notably, the formation of pyridinium-carboxylate adducts in the salts does not appear to be strongly correlated with acid pKa. Three distinct network topologies were observed, and all featured the bridging of two or three tetra(pyridyl)ethylene groups through di-acid linkers. Crystalline assemblies also retained the AIE activity of tetra(pyridyl)ethylene and were luminescent under UV light. As tetra(4-pyridyl)ethylene features four Lewis basic and potentially metal ligating pyridine rings in a relatively well-defined geometry, this compound represents an attractive building block for the design of additional crystalline organic and metal–organic functional materials

Multitarget therapeutic strategies for Alzheimer’s disease

Neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s diseases have multifaceted nature because of the different factors contributing to their progression. The complex nature of neurodegenerative diseases has developed a pressing need to design multitarget-directed ligands to address the complementary pathways involved in these diseases. The major enzyme targets for development of therapeutics for Alzheimer’s disease are cholinesterase and β-secretase enzymes. In this review, we discuss recent advances in profiling single target inhibitors based on these enzymes to multitarget-directed ligands as potential therapeutics for this devastating disease. In addition, therapeutics based on iron chelation strategy are discussed as well

Pharmacophore-based tailoring of biphenyl amide derivatives as selective 5-hydroxytryptamine 2B receptor antagonists

We designed and synthesized a new biphenyl amide-tryptamine hybrid molecule 7 utilizing a pharmacophore-based approach as a 5-HT antagonist. The hybrid compound 7 was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT receptor. Functional assays revealed potent antagonism of 5-HT by 7 with an IC value of 14.1 nM. Moreover, compound 7 possessed a desirable in vitro pharmacokinetic profile and maintained its antagonistic potency in the presence of physiological concentrations of serum proteins. The design approach implemented in this investigation would facilitate the development of a second generation of highly selective and potent 5-HT antagonists

Synthesis, antiproliferative activity and autophagic flux inhibition of new arylsparteine derivatives

New series of arylsparteine derivatives were synthesized and evaluated for their cytotoxic activity against four human cancer cell lines (cervical epithelial carcinoma cells Hela, breast cancer cells MCF-7, lung cancer cells A549, and glioma cells U87 MG) and one normal fibroblast cell line. Structure-activity relationship revealed that introduction of 4-quinolinyl moiety to sparteine afforded a hybrid compound 10 with considerable antiproliferative activity against all tested cancer cell lines. Compound 10, the most active agent in this study possessed IC50 values of 5.97 +/- 1.1 and 9.52 +/- 0.3 mu M against A549 and Hela cancer cell lines, respectively. Inhibition of autophagic flux proved to be the underlying mechanism for the antiproliferative activity of 10 which was further validated by decreased levels of ATP in cancer cells treated with 10. In addition, co-treatment of 10 and rapamycin restored cell viability which comes in good agreement with the proposed autophagic flux inhibition for 10

Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors

Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC value of 4.11 nM) and BACE-1 inhibition (IC value of 18.3 nM) in comparison to donepezil (IC values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease

Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors

A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC value of 14.7 nM) and BACE-1 inhibition (IC value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied