Novel alkyl-substituted 4-methoxy benzaldehyde thiosemicarbazones: Multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting mental ability and interrupts neurocognitive functions. Treating multifactorial conditions of AD with a single-target-directed drug is highly difficult. Thus, a multi-target-directed ligand (MTDL) development strategy has been developed as a promising approach for the treatment of AD. Herein, we have synthesized two novel thiosemicarbazones as MTDLs and reported their bioactivities against diverse neuropathological events involved in AD. In vitro studies revealed that both compounds exhibited promising anticholinesterase activity (AChE, IC50 = 15.98 µM, MZET and IC50 = 30.23 µM, MZMT), well supported by a detailed computational study. Both analogs have shown good thermodynamic behaviour and stability through interactions with characteristic amino acid residues throughout simulation of 100 ns against acetylcholinesterase enzyme. In an electrophysiology assay, these analogs have shown a characteristic inhibitory response against the GluN1-1a + GluN2B subunit of N-methyl-D-aspartate receptors. Pre-treatment of BV-2 microglial cells with MZET effectively decreased nitrite production compared to nitrite produced by lipopolysaccharide-treated cells alone. Further, the effect of MZMT and MZET on autophagy regulation was determined using stably transfected SH-SY5Y neuroblastoma cells. MZET significantly enhanced the autophagy flux in neuroblastoma cells. A significant decrease in copper-catalysed oxidation of amyloid-ß in presence of synthesized thiosemicarbazones was also observed. Collectively, our findings indicated that these analogs have potential as effective anti-AD candidates and can be used as a prototype to develop more safer multi-targeted anti-AD drugs.

Construction of Pyrazine-Appended 1D and 3D Cobalt(II) Succinate Coordination Polymers: Influence of Solvent on Architectures and Applications in Gas Adsorption and NAC Detection.

An underexplored reaction of pyrazine (rigid and linear) and succinic acid (flexible) with Co(NO3)2·6H2O afforded four new coordination polymers (CPs): [Co(H2O)(pyz)(suc)] (1), [Co(H2O)2(pyz)(suc)] (2), [Co(H2O)4(pyz)](suc) (3) and [Co2(H2O)2(pyz)(suc)2] (4), as well as [Co(HCO2)2(pyz)] (5) being lately reported along with well-known 6 and 7. The CPs were obtained as stable crystalline materials and characterized by conventional solid-state techniques, including X-ray crystallography. Hydrothermally produced compounds 1 and 2 were both 3D CPs. While 3 and 4 obtained under ambient/solvothermal conditions in DMSO generated 1D and 3D structures, 5 isolated from DMF under solvothermal conditions had a 3D structure. The topologies of the coordination polymers 1-7 were described by underlying nets 3D 5-c fet, 3D 4-c cds, 1D 2-c 2C1, 3D 5-c bnn, 3D 6-c rob, 1D 2-c 2C1, and 3D 6-c pcu, respectively. The plot of χM -1 versus T was essentially linear in the entire temperature range following the Curie-Weiss law with a Curie constant (C) of 2.525 and a negative Weiss constant (ϕ) of -46.24 K, suggesting weak antiferromagnetic (AF) exchange interactions. CO2 and N2 adsorption studies of 1-5 featured type III isotherms. 1 was found to show remarkably higher quenching efficiencies for nitrophenols (η = 98% for o-NP) over other NACs. The Stern-Volmer plot exhibited deviation in linearity with K sv values about 200 times greater than that for the simplest nitroaromatic compound (NB), signifying its exclusive quenching ability toward 1. The LOD for p-NP addition to 1 was found to be 0.995 ppm.

Coordination polymers of CdII and PbII derived from bipyridine-glycoluril: influence of metal-ion size and counter-ions.

Two new one-dimensional (1D) coordination polymers (CPs), namely catena-poly[[[aquacadmium(II)]-bis(µ-4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione)] bis(perchlorate) dihydrate], {[Cd(C14H10N6O2)2(H2O)](ClO4)2·2H2O}n or {[Cd(BPG)2(H2O)](ClO4)2·2H2O}n, 1, and catena-poly[[lead(II)-bis(µ-4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione)] bis(perchlorate) dihydrate], {[Pb(C14H10N6O2)2](ClO4)2·2H2O}n or {[Pb(BPG)2](ClO4)2·2H2O}n, 2, have been synthesized using bipyridine-glycoluril (BPG; systematic name: 4b,5,7,7a-tetrahydro-4b,7a-epiminomethanoimino-6H-imidazo[4,5-f][1,10]phenanthroline-6,13-dione), a urea-fused tecton, in a mixed-solvent system. The CdII ion in 1 is heptacoordinated and the PbII ion in 2 is hexacoordinated, with the CdII ion adopting a pentagonal bipyramidal geometry and the PbII ion adopting a distorted octahedral geometry. Both CPs form infinite linear chain structures which are hydrogen bonded to each other leading to the formation of three-dimensional supramolecular network structures. Topological analysis of CPs 1 and 2 reveals that the structures exhibit 1D chain-like arrangements in an AB-AB sequence and shows platonic uniform 2-connected uninodal topologies. Furthermore, a comparative analysis of a series of structures based on the BPG ligand indicates that the size of the metal ion and the types of counter-ions used have a great influence on the resulting frameworks and properties.

A copper(ii)-coordination polymer based on a sulfonic-carboxylic ligand exhibits high water-facilitated proton conductivity.

Proton conduction ability has been investigated in a new Cu(ii) based coordination polymer (CP), {[Cu2(sba)2(bpg)2(H2O)3]·5H2O}n (1), synthesized using the combination of 4-sulfobenzoic acid (4-Hsba) and bipyridine-glycoluril (BPG) ligands. Single crystal X-ray structure determination revealed that 1 features 1D porous channels encapsulating a continuous array of water molecules. Proton conductivity measurements reveal a high conductivity value of 0.94 × 10-2 S cm-1 at 80 °C and 95% RH. The activation energy (Ea) of 0.64 eV demonstrates that the solvate water, coordinated water and hydrophilic groups in the channels promote the mobility of protons in the framework. Water sorption measurements exhibited hysterical behaviour with a high uptake value of 379.07 cm3 g-1. Time-dependent measurements revealed that the proton conductivity is retained even after 12 h of measurements. The proton conduction mechanism was validated by ab initio electronic structure calculations using the Nudged Elastic Band (NEB) method with molecular dynamics (MD) simulation studies. The theoretical activation energy is calculated to be 0.54 eV which is in accordance with the experimental value.

Heterostructural CuO-ZnO Nanocomposites: A Highly Selective Chemical and Electrochemical NO2 Sensor.

A simple one-step chemical method is employed for the successful synthesis of CuO(50%)-ZnO(50%) nanocomposites (NCs) and investigation of their gas sensing properties. The X-ray diffraction studies revealed that these CuO-ZnO NCs display a hexagonal wurtzite-type crystal structure. The average width of 50-100 nm and length of 200-600 nm of the NCs were confirmed by transmission electron microscopic images, and the 1:1 proportion of Cu and Zn composition was confirmed by energy-dispersive spectra, i.e., CuO(50%)-ZnO(50%) NC studies. The CuO(50%)-ZnO(50%) NCs exhibit superior gas sensing performance with outstanding selectivity toward NO2 gas at a working temperature of 200 °C. Moreover, these NCs were used for the indirect evaluation of NO2 via electrochemical detection of NO2 - (as NO2 converts into NO2 - once it reacts with moisture, resulting into acid rain, i.e., indirect evaluation of NO2). As compared with other known modified electrodes, CuO(50%)-ZnO(50%) NCs show an apparent oxidation of NO2 - with a larger peak current for a wider linear range of nitrite concentration from 20 to 100 mM. We thus demonstrate that the as-synthesized CuO(50%)-ZnO(50%) NCs act as a promising low-cost NO2 sensor and further confirm their potential toward tunable gas sensors (electrochemical and solid state) (Scheme 1).

Proton conduction in a hydrogen-bonded complex of copper(ii)-bipyridine glycoluril nitrate.

Bipyridine glycoluril (BPG), a urea-fused bipyridine tecton, forms a square-pyramidal secondary building unit with copper(ii) which further self-assembles to give a porous hydrogen-bonded complex. This complex displays a high proton conductivity of 4.45 × 10-3 S cm-1 at 90 °C and 95% relative humidity (RH). Chains consisting of coordinated water, solvent water and nitrate anions embedded in the complex are responsible for high proton conduction. The proton conduction pathway was corroborated by ab initio electronic structure calculations with molecular dynamics (MD) simulations using the Nudged Elastic Band (NEB) method. The theoretical activation energy estimated to be 0.18 eV is in close agreement with the experimental value of 0.15 eV which evidences a Grotthuss proton hopping mechanism. We thus demonstrate that the hydrogen-bonded complex encapsulating appropriate counter ions, coordinated water and solvent water molecules exhibts superprotonic conductivity.