Design, synthesis and biological assessment of acridine derivatives containing 1,3,4-thiadiazole moiety as novel selective acetylcholinesterase inhibitors.

A novel series of acridine derivatives containing substituted thiadiazol-2-amine moiety was synthesized via multi-component condensation reaction of dimedone, aromatic aldehyde and 5-aryl-1,3,4-thiadiazol-2-amines in the presence of LaCl3 as a catalyst under solvent-free conditions. Anticholinesterase (AChE and BuChE) activity evaluation of the derivatives showed that all the derivatives are capable of inhibiting both enzymes and are highly selective towards AChE. Among them, the ability of 4i and 4d with respective IC50 values of 0.002 and 0.006 µM to inhibit AChE was higher than the reference compound tacrine (IC50 = 0.016 µM). The kinetics studies demonstrated that 4i and 4d inhibit AChE through a competitive/non-competitive mixed mechanism. The HEPG2 cell viability assay evidenced that 4i and 4d significantly exhibit lower hepatotoxicity compared with tacrine. Blind docking experiments performed on TcAChE (PDB ID: 2ACE) indicated that an unknown site is preferred for binding by all the derivatives over classic binding site of the enzyme, site 1 (CAS/PAS). Identification of the residues by protein structure alignment confirmed that this site is site 2 which was recently recognized as a new allosteric site of hAChE. The binding modes of 4i and 4d were also investigated using local docking studies on site 1 and site 2.

Pharmacoeconomics of dementia.

Pharmacoeconomics is a new discipline with its own terminology and techniques, little known to most clinicians but destined to become more important to them and to their patients. This article reviews basic approaches in pharmacoeconomics; current knowledge of costs related to dementia; assessment of quality of life in patients with cognitive impairment; models of relationships among degree of cognitive impairment, caregiver burden, and health care utilization; existing pharmacoeconomic guidelines for drug studies; pharmacoeconomic studies of tacrine, a drug used in Alzheimer disease; and further work needed to advance the critical area of pharmacoeconomic studies in dementia.