Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

• Keywords
• Alzheimer’s disease, N-methyl-d-aspartate receptor, acetylcholinesterase, butyrylcholinesterase, fluorene, in silico, in vitro, multi-target directed ligands,
• MeSH
• Alzheimer Disease drug therapy   enzymology   genetics   pathology   MeSH
• Butyrylcholinesterase chemistry   drug effects   genetics   MeSH
• CHO Cells MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Cricetulus MeSH
• Fluorenes chemistry   pharmacology   MeSH
• Blood-Brain Barrier drug effects   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Humans MeSH
• Computer Simulation MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• fluorene MeSH Browser
• Fluorenes MeSH
• Enzyme Inhibitors MeSH
• N-methyl D-aspartate receptor subtype 2A MeSH Browser
• NR2B NMDA receptor MeSH Browser
• Receptors, N-Methyl-D-Aspartate MeSH

A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.

• Keywords
• 7-MEOTA-tacrine heterodimers, HL-60, calf thymus DNA, human dermal fibroblasts, topoisomerases,
• MeSH
• Acridines chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Fibroblasts drug effects   MeSH
• HL-60 Cells MeSH
• Humans MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Tacrine chemistry   pharmacology   MeSH
• Thiourea chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
• Acridines MeSH
• Antineoplastic Agents MeSH
• Tacrine MeSH
• Thiourea MeSH

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

• Keywords
• Acetylcholinesterase, Alzheimer’s disease, donepezil, multi-target directed ligands, oxidative stress,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   pharmacology   MeSH
• Donepezil MeSH
• Indans chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Piperidines chemistry   pharmacology   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Antioxidants MeSH
• Cholinesterase Inhibitors MeSH
• Donepezil MeSH
• Indans MeSH
• Piperidines MeSH