Send Orders of Reprints at reprints@benthamscience.net Letters in Organic Chemistry, 2013, 10, ???-??? 1 1570-1786/13 $58.00+.00 © 2013 Bentham Science Publishers Comparison of Novel Tacrine and 7-MEOTA Derivatives with Aromatic and Alicyclic Residues: Synthesis, Biological Evaluation and Docking Studies Jan Korabecny a,b , Ladislav Janovec c , Kamil Musilek a,b,d , Filip Zemek b , Anna Horova b , Eugenie Nepovimova e , Rafael Dolezal a , Veronika Opletalova e , Jana Hroudova f , Zdenek Fisar f , Young-Sik Jung g and Kamil Kuca a,d,h* a University Hospital, Biomedicinal Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; b Depart- ment of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; c Department of Organic Chemistry, Institute of Chemistry, Faculty of Science, P.J. afárik University, Moyzesova 11, 041 67 Kosice, Slovak Republic; d Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, Roki- tanskeho 62, 500 03 Hradec Kralove, Czech Republic; e Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; f Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General Uni- versity Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic; g Medicinal Science Division, Korea Re- search Institute of Chemical Technology, PO Box 107, Yusong, Taejon 305-606, Republic of Korea; h Centre of Ad- vanced Studies, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic Received June 08, 2012: Revised October 17, 2012: Accepted October 18, 2012 Abstract: Cholinesterase inhibitors play an essential role in the treatment of Alzheimer’s disease. Since their first intro- duction over a decade ago, they are an indispensable part of Alzheimer’s disease therapy and remain at the forefront of scientific interest worldwide. In this manuscript new analogs of THA and 7-MEOTA were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase and butyrylcholinesterase. Cholinergic properties were investigated and quantified with respect to their side chain residues (aromatic or alicyclic). All synthesized com- pounds proved to have potent inhibitory activity at micromolar range. Moreover, compound 4 demonstrated promising ef- ficacy and appears to be an ideal candidate for further testing. Keywords: 7-methoxytacrine, acetylcholinesterase, Alzheimer`s disease, butyrylcholinesterase, inhibition selectivity, molecu- lar modelling. INTRODUCTION Alzheimer`s disease (AD) is a multifactorial impairment and one of the most common forms of neurodegenerative illnesses affecting approximately 10% of the population over the age of 65 years and nearly 50% of those older than 85 years of age. At the moment, two major therapeutic strate- gies have been developed for the treatment of AD. The first strategy is inspired by the amyloid hypothesis. It basically describes with the aggregation of monomeric peptide (A) into larger oligomeric and fibrillar forms. Aggregation of -amyloid is seen as a significant step in the AD pathology and cognitive loss. Thereby treatment focuses on prevention of -amyloid formation and subsequent deposition in the form of plaques. Certain evidence suggests that this can be an early and obligatory event in the pathogenesis of AD [1, 2]. Based on the second strategy called “cholinergic hy- pothesis”, many attempts have been made to reverse * Address correspondence to this author at the Centre of Advanced Studies, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; Tel: +420 973 253 028; Fax: +420 495 513 018; E-mail: kucakam@pmfhk.cz cognitive deficits by increasing brain cholinergic activity through the use of cholinomimetics such as cholinesterase inhibitors (ChEIs), acetylcholine (ACh) precursors, and di- rect cholinergic agonists. Although the decline of cholinergic neurotransmission is most probably a downstream process of AD pathophysiology until now the only therapeutic interven- tion uses (apart from the N-methyl-D-aspartate (NMDA) antagonist memantine; (Fig. 1) acetylcholinesterase inhibi- tors (AChEIs) as the best clinically relevant approach for stabilizing memory and cognitive decline in AD patients [3, 4]. This assumption led to the introduction of 9-amino- 1,2,3,4-tetrahydroacridine (tacrine, THA; trade name Cognex ® , USP Sciele Pharm Inc) as the first AChEI specifi- cally approved for the treatment of AD in 1993 [5]. THA approval was followed by other AChEIs e.g. donepezil (1997; trade name Aricept ® , Eisai Company and Pfizer Inc.), rivastigmine (2000; trade name Exelon ® , Novartis Pharma- ceuticals) and galantamine (2001; Hoechst Marion Roussel Inc., Shire Pharmaceutical Group, and Janssen Pharmaceuti- cal, trade names Reminyl ® and Nivalin ® , U.S. trade name Razadyne ® ) (Fig. 1). Focused on THA, large number of patients withdrew dur- ing the trials with this drug, many because of THA-