Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease.

A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). Most of the compounds were good AChE inhibitors (IC50 = 9.8-0.71 µM) and showed remarkable BuChE inhibition activity (IC50 = 1.9-0.006 µM) compared with donepezil as the standard drug (IC50 = 0.023 and 3.4 µM). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50 = 0.71 µM) and BuChE (IC50 = 0.006 µM), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on H2O2- and Aß-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced Aß aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.

Magnetic nanoparticles decorated with PEGylated curcumin as dual targeted drug delivery: Synthesis, toxicity and biocompatibility study.

The problems associated with hydrophobic anticancer drugs are among the most important challenges to achieve efficient therapeutics for cancer treatment. In this study, PEGylated curcumin was used as the surface modification of magnetic nanoparticles (MNP@PEG-Cur) in order to simultaneously take advantage of magnetic targeting characteristic of nanoparticles and PEG conjugated drug. Curcumin was conjugated through EDC/NHS chemistry to the PEG hydroxyl functional groups, and then physically decorated on the surface of magnetic nanoparticles (MNP). The analysis of the conjugate and nanoparticles by FT-IR, 1HNMR, FE-SEM, TEM, EDX, TGA and VSM confirmed the successful synthesis and proper physicochemical properties of MNP@PEG-Cur nanoparticles. The carrier showed pH dependent drug release profile with higher drug release at acidic media (pH = 5.4) compared to neural condition (pH = 7.4). In addition, LD50 and hemolysis assay confirmed the biocompatibility of MNP@PEG-Cur. The cell viability assay also revealed that neither carrier, nor curcumin-loaded nanoparticles are cytotoxic at physiologic pH (7.4).

A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia, is a multifactorial neurodegenerative disease. The target enzymes inhibition including cholinesterase, beta-secretase, monoamine oxidase and inhibition of amyloid-ß aggregation as well as oxidative stress and metal chelation play an important role in the pathogenesis of AD. Chroman-4-one scaffold with benzo-γ-pyrone network is a privileged structure in organic synthesis and drug design. A large number of research has been carried out on modified naturally occurring chromanone scaffolds and/or synthesized new analogues, to obtain effective drugs for AD management. The present review summarizes aspects related to the multi-target-directed ligands (MTDLs) strategy in enzyme targets modulation performed with natural and synthesized chroman-4-one-based structures to look at their potential in the management of multifactorial Alzheimer's disease.