Novel Hybrid Inhibitors of Cholinesterases as Potential Anti-Alzheimer Agents

Alzheimer`s disease (AD) is the most prominent form of dementia affecting worldwide about 9% of the population aged over 65 and the number of patients will rise to estimated 81.1 million by 2040 [1]. AD is a multifactorial disease and several theories about its pathogenesis are discussed, mostly including the ß-amyloid cascade [2], the tau-protein hyperphosphorylation hypothesis [3], oxidative stress, free radical formation and neuroinflammation [4]. Today’s medication is based on the cholinergic hypothesis, asserting that a decline of acetylcholine (ACh) in the brain leads to cognitive and memory deficits. The level of ACh is regulated by cholinesterases (ChEs), namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). A therapeutic approach is to inhibit these two hydrolytic enzymes. Well known AChE inhibitors are tacrine, donepezil, galantamine and rivastigmine, with tacrine being the most potent derivative in the series [5]. Unfortunately, the use of tacrine is currently limited by its serious hepatotoxicity [6] and the clinical effectiveness of AChEIs is still under debate [7]. It is therefore desirable to develop new and highly effective drugs for AD. Promising candidates are bipharmacophoric hybrid compounds in which the inhibitory potency of tacrine can be combined with other pharmacological benefits, such as reduced hepatotoxicity [8]. In this context, compound 1, consisting of tacrine and the muscarinic superagonist iperoxo [9] (imitating the endogenous ligand ACh) linked by a C10 polymethylene spacer, was found to have excellent anticholinesterase activities for both AChE (IC50 = 0.155 nM) from electric eel and isolated rat brain as well as for BChE (IC50 = 1.797 nM) from equine serum, respectively. Additionally, this hybrid shows less cytotoxicity than the corresponding tacrine-related dimers. Docking experiments provide a structural model to rationalize the inhibitory power towards AChE. Compound 1 is a promising candidate for further drug development investigations. Acknowledgments: Thanks are due to the Institute for Molecular Infection Biology of the University of Würzburg (Germany) for evaluation of the cytotoxicity of the tacrine-related compounds. References: 1. Deutsche Alzheimer Gesellschaft, Factsheet 2014. 2. Hardy, J.: J. Neurochem. 2009, 110(4): 1129-1134. 3. Bulic, B. et al.: Angew. Chem. Int. Ed. Engl. 2009, 48(10): 1740-1752. 4. Gella A., Durany, N.: Cell Adh. Migr. 2009, 3(1): 88-93. 5. Grimmer T., Kurz A.: Drugs Aging 2006, 23(12): 957-967. 6. Watkins, P.B. et al.: JAMA: J. Am. Med. Assoc. 1994, 271(13): 992-998. 7. Munoz-Torrero D.: Curr. Med. Chem. 2008, 15(24), 2433-2455. 8. Nepovimova E. et al.: J. Med. Chem. 2015, 58(22): 8985-9003. 9. Schrage R. et al.: Br. J. Pharmacol. 2013, 169(2): 357-370.