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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis of Tacrine Analogues Comprising a Peptide MoietyDantcho L. Danalev 1 , Lyubomir T. Vezenkov 1 , and Nikolay Vassilev 21 University of Chemical Technology and Metallurgy, Department of Organic Chemistry,Sofia, Bulgaria, dancho_danalev@yahoo.com; 2 Institute of Organic Chemistry,Bulgarian Academy of Sciences, Sofia, BulgariaIntroductionAlzheimer’s disease (AD) is a neurodegenerative illness, which affects millions of peopleworldwide. According to World Health Organization around 26.6 million peopleworldwide had AD in 2006. As of September 2009, this number is reported to be 35million-plus worldwide. Following the dynamic development of the disease this numbermay quadruple by 2050.AD is characterized by progressive dementia, loss of memory, intellectual, speech andbrain disturbances and inevitably leads to complete personality decay and a lethal outcome.The cause and progression of AD are not well understood. In recent years research has beenfocused on AD to clarify the mechanisms of development of the disease and to establish thereasons for its occurrence. Designating neuropathological lesions associated with all formsof AD are senile plaques (SPs), and amyloid angiopathy as well as neurofibril tangles(NFTs).Today a most useful approach for the treatment of AD in a medical practice is torestore the level of acetylcholine by inhibiting AChE with reversible inhibitors [1]. Few ofthese inhibitors may pass into the brain and remain effective without serious side effects[2]. There are significant differences in the mechanisms of action of various cholinesteraseinhibitors [3]. As of 2008, the cholinesterase inhibitors approved for the management ofAD symptoms are donepezil (brand name Aricept), galantamine (Razadyne), andrivastigmine (branded as Exelon and Exelon Patch).Clinical trials have shown that acetylcholinesterase inhibitors as tacrine (1,2,3,4-tetrahydro-9-akridinamin) and physostigmine ((3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimetilpirolo[2,3-b]indole-5-ol methylcarbamate (ester)) effectively improve the memoryof some patients [1,2]. Tacrinе, although weaker than physostigmine, is more useful in thetreatment of AD. Its uses lead to improvement in orientation, the total assessment forlearning and testing, but just like physostigmine it causes side effects [2]. Unfortunately,the use of tacrinе is limited by poor oral bioavailability, the necessity for four-times dailydosing, and considerable adverse drug reactions (including nausea, diarrhea, urinaryincontinence and hepatotoxicity) such that few patients could tolerate therapeutic doses [4].Results and DiscussionHerein, we report for the synthesis of a series of hybrid analogs of tacrine molecule andpeptide fragments (Figure 1). This is aimed at obtaining the hybrid molecules withcombined pharmacological effect, acetylcholinesterase inhibitory activity due to themolecule of tacrine and γ-secretase inhibitory activity due to the peptide fragment.Additionally, we tried to reduce the high toxicity of some tacrine analogues, well knownfrom the literature, using peptide fragments. Moreover, a series of analogues containing a“spacer” of 6-aminohexanoic acid between two active parts of hybrid molecules wassynthesized.Taking into account our previous experience with the synthesis of hybrid analogues ofthe acetylcholinesterase inhibitor, based on galanthamine molecule [5], we used peptideanalogues of 3,5-dichlorophenylalanine with proven γ-secretase inhibitory activity [6](Figure 2).In addition, for the purposes of our study, a residue of 6-aminohexanoic acid methylester was linked to peptide derivatives of N-(3,5-dichlorophenyl)-D, L-alanine, the resultingesters were hydrolyzed using 2N NaOH to corresponding free acids with the generalformula presented in Figure 3. The structure of final hybrid molecules comprising linker of6-aminohexanoic acid is presented in Figure 4.All compound structures were proven with 1 H, 13 C and 2D NMR recorded on AvanceAV II+ spectrometer at 600.13 MHz for 1 H and CDCl 3 as solvent. The reaction progresswas monitored on TLC using the following systems 3:1:1 (n-BuOH:AcOH:H 2 O) for estersand 8:2 or 1:1 (ethylacetate:hexane) for all other compounds. The reactions of hydrolysis of302