A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

Department of Toxicology Trebesska 1575 Faculty of Military Health Sciences University of Defence 50001 Hradec Kralove Czech Republic

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Lipton S.A. The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: Low-affinity, Uncompetitive antagonism. Curr. Alzheimer Res. 2005;2:155–165. doi: 10.2174/1567205053585846. PubMed DOI

Dominguez E., Chin T.Y., Chen C.P., Wu T.Y. Management of moderate to severe Alzheimer’s disease: Focus on memantine. Taiwan J. Obstet. Gynecol. 2011;50:415–423. doi: 10.1016/j.tjog.2011.10.004. PubMed DOI

Benzi G., Moretti A. Is there a rationale for use of acetylcholinesterase inhibitors in the therapy of Alzheimer’s disease? Eur. J. Pharmacol. 1998;346:1–13. doi: 10.1016/S0014-2999(98)00093-4. PubMed DOI

Walsh D.M., Selkoe D.J. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron. 2004;44:181–193. doi: 10.1016/j.neuron.2004.09.010. PubMed DOI

Belluti F., Bartolini M., Bottegoni G., Bisi A., Cavalli A., Andrisano V., Rampa A. Benzophenone-based derivatives: A novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. Eur. J. Med. Chem. 2011;46:1682–1693. doi: 10.1016/j.ejmech.2011.02.019. PubMed DOI

Scarpini E., Scheltens P., Feldman H. Treatment of Alzheimer’s disease: Current status and new perspectives. Lancet Neurol. 2003;2:39–47. PubMed

Shan W.J., Huang L., Zhou Q., Meng F.C., Li X.S. Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multifunctional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation. Eur. J. Med. Chem. 2011;46:5885–5893. PubMed

Guo T., Hobbs D.W. Development of BACE1 inhibitors for Alzheimer’s disease. 2006;13:1811–1829. PubMed

Zhu Y., Xiao L., Xiong B., Fu Y., Yu H., Wang W., Wang X., Hu D., Peng H., Li J., et al. Design, Synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase. Bioorg. Med. Chem. 2009;17:1600–1613. PubMed

Bartus R.T., Dean 3rd R.L., Beer B., Lippa A.S. Thee cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–414. PubMed

Terry A.V., Jr., Buccafusco J.J. The cholinergic hypothesis age and Alzheimer’s disease- related cognitive deficits: Recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther. 2003;306:821–827. doi: 10.1124/jpet.102.041616. PubMed DOI

Whitehouse P.J. Cholinergic therapy in dementia. Acta Neurol. Scand. Suppl. 1993;149:42–45. PubMed

Kelly C.A., Harvey R.J., Cayton H. Drug treatments for Alzheimer’s disease. BMJ. 1997;314:693–694. doi: 10.1136/bmj.314.7082.693. PubMed DOI PMC

Scott L.J., Goa K.L. Galantamine: A review of its use in Alzheimer’s disease. Drug. 2000;60:1095–1122. doi: 10.2165/00003495-200060050-00008. PubMed DOI

Bielavsky J. Analogues of 9-amino-1,2,3,4-tetrahydroacridine. Collect. Czech. Chem. Commun. 1977;42:2802–2808. doi: 10.1135/cccc19772802. DOI

Yan A., Wang K. Quantitative structure and bioactivity relationship study on human acetylcholinesterase inhibitors. Bioorg. Med. Chem. Lett. 2012;22:3336–3342. doi: 10.1016/j.bmcl.2012.02.108. PubMed DOI

Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst. Rev. 2006:CD005593. PubMed PMC

McShane R., Areosa Sastre A., Minakaran N. Memantine for dementia. Cochrane Database Syst. Rev. 2006:CD003154. PubMed

Weiner M.W., Sadowsky C., Saxton J., Hofbauer R.K., Graham S.M., Yu S.Y., Li S., Hsu H.A., Suhy J., Fridman M., et al. Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer’s disease. Alzheimers Dement. 2011;7:425–435. PubMed

Munoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer’s disease. Curr. Med. Chem. 2008;15:2433–2455. doi: 10.2174/092986708785909067. PubMed DOI

Chen H.S., Pellegrini J.W., Aggarwall S.K., Lei S.Z., Warach S., Jensen F.E., Lipton S.A. Open-channel block of N-metyhl-D-aspartate (NMDA) responses by memantine: Therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 1992;12:4427–4436. PubMed PMC

Parson C.G., Danysz W., Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—A review of preclinical data. Neuropharmacology. 1999;38:735–767. doi: 10.1016/S0028-3908(99)00019-2. PubMed DOI

Wu H.M., Tzeng N.S., Qian L., Wei S.J., Hu X., Chen H.S., Rawls S.M., Flood P., Hong J.S., Lu R.B. Novel neuroprotective mechanisms of memantine: increase in neurotropic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology. 2009;34:2344–2357. PubMed PMC

Kim J.H., Lee H.W., Hwang J., Kim J., Lee M.J., Han H.S., Lee W.H., Suk K. Microglial-inhibiting activity of Parkinson’s disease drug amantadine. Neurobiol. Aging. 2012;33:2145–2159. doi: 10.1016/j.neurobiolaging.2011.08.011. PubMed DOI

Kornhuber J., Bormann J., Hübers M., Rusche K., Riederer P. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: A human postmortem brain study. Eur. J. Pharmacol. 1991;206:297–300. doi: 10.1016/0922-4106(91)90113-V. PubMed DOI

Inzelberg R., Bonuccelli U., Schechtman E., Miniowich A., Strugatsky R., Ceravolo R., Logi C., Rossi C., Klein C., Rabey J.M. Association between amantadine and the onset of dementia in Parkinson’s disease. Mor. Disord. 2006;21:1375–1379. doi: 10.1002/mds.20968. PubMed DOI

Robinson D.M., Keating G.M. Memantine: A review of its use in Alzheimer’s disease. Drugs. 2006;66:1515–1534. doi: 10.2165/00003495-200666110-00015. PubMed DOI

Dejmek L. 7-MEOTA. Drug. Future. 1990;15:126.

Watkins P.B., Zimmerman H.J., Knapp M.J., Gracon S.I., Lewis K.W. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994;271:992–998. PubMed

Patocka J., Jun D., Kuca K. Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer’s disease. Curr. Drug. MeTable. 2008;9:332–335. doi: 10.2174/138920008784220619. PubMed DOI

Korabecny J., Musilek K., Zemek F., Horova A., Holas O., Nepovimova E., Opletalova V., Hroudova J., Fisar Z., Jung Y.S., et al. Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine—New tacrine derivative with cholinergic properties. Bioorg. Med. Chem. Lett. 2011;21:6563–6566. PubMed

Korabecny J., Musilek K., Holas O., Nepovimova E., Jun D., Zemek F., Opletalova V., Patocka J., Dohnal V., Nachon F., et al. Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer’s disease treatment. Molecules. 2010;15:8804–8812. PubMed PMC

Korabecny J., Musilek K., Holas O., Binder J., Zemek F., Marek J., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg. Med. Chem. Lett. 2010;20:6093–6095. PubMed

Korabecny J., Holas O., Musilek K., Pohanka M., Opletalova V., Dohnal V., Kuca K. Synthesis and in vitro evaluation of new tacrine derivatives—Bis-alkylene linked 7-MEOTA. Lett. Org. Chem. 2010;7:327–331. doi: 10.2174/157017810791130540. DOI

Youdim M.B., Buccafusco J.J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 2005;26:27–35. doi: 10.1016/j.tips.2004.11.007. PubMed DOI

Cavalli A., Bolognesi M.L., Minarini A., Rosini M., Tumiatti V., Recanatini M., Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 2008;51:347–372. PubMed

Kozurkova M., Hamulakova S., Gazova Z., Paulikova H., Kristian P. Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties. Pharmaceuticals. 2011;4:382–418. doi: 10.3390/ph4020382. DOI

Melchiorre C., Andrisano V., Bolognesi M.L., Budriesi R., Cavalli A., Cavrini A., Rosini M., Tumiatti V., Recanatini M. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer’s disease. J. Med. Chem. 1998;41:4186–4189. PubMed

Sterling J., Herzig Y., Goren T., Finkelstein N., Lerner D., Goldenberg W., Miskolezi I., Molnar S., Rantal F., Tamas T., et al. Novel dual inhibitors of AchE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer’s disease. J. Med. Chem. 2002;45:5260–5279. PubMed

Zheng H., Amit T., Bar-Am O., Fridkin M., Youdim M.B., Mandel S.A. From anti-Parkinson’s drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer’s disease. J. Alzheimers Dis. 2012;30:1–16. PubMed

Weinreb O., Amit T., Bar-Am O., Youdim M.B. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain- selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr. Drug Targets. 2012;13:483–494. doi: 10.2174/138945012799499794. PubMed DOI

Kogen H., Toda N., Tago K., Marumoto S., Takami K., Ori M., Yamada N., Koyama K., Naruto S., Abe K., et al. Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter targeting potential agents for Alzheimer’s disease. Org. Lett. 2002;4:3359–3362. PubMed

Toda N., Kaneko T., Kogen H. Development of an efficient therapeutic agent for Alzheimer’s disease: Design and synthesis of dual inhibitors of acetylcholinesterase and serotonin transporter. Chem. Pharm. Bull. (Tokyo) 2011;58:273–287. PubMed

Cavalli A., Bolognesi M.L., Capsoni S., Andrisano V., Bartolini M., Margotti E., Cattaneo A., Recanatini M., Melchiorre C. A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew. Chem. Int. Ed. Engl. 2007;46:3689–3692. PubMed

Hamulakova S., Janovec L., Hrabinova M., Kristian P., Kuca K., Banasova M. Synthesis, Design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2012;55:23–31. doi: 10.1016/j.ejmech.2012.06.051. PubMed DOI

Di Santo R., Costi R., Cuzzucoli Crucitti G., Pescatori L., Rosi F., Scipione L., Celona D., Vertechy M., Ghirardi O., Piovesan P., et al. Design, Synthesis, and Structure—activity relationship of N-arylnaphtylmine derivatives as amyloid aggregation inhibitors. J. Med. Chem. 2012;55:8538–8548. PubMed

Chen Y., Sun J., Fang L., Liu M., Peng S., Liao H., Lehmann J., Zhang Y. Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids os potent, multifunctional acetyl- and butyrylcholinesterase inhibitors. J. Med. Chem. 2012;55:4309–4321. doi: 10.1021/jm300106z. PubMed DOI

Fernandez-Bachiller M.I., Perez C., Monjas L., Rademann J., Rodriguez-Franco M.I. New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with cholinergic, Antioxidant, and β-amyloid-reducing. J. Med. Chem. 2012;55:1303–1317. PubMed

Galdeano C., Viayna E., Sola I., Formosa X., Camps P., Badia A., Clos M.V., Relat J., Ratia M., Bartolini M., et al. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion disease. J. Med. Chem. 2012;55:661–669. PubMed

Bolognesi M.L., Cavalli A., Valgimigli L., Bartolini M., Rosini M., Andrisano V., Recanatini M., Melchiorre C. Multi-target-directed drug design strategy: From a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J. Med. Chem. 2007;50:6446–6449. doi: 10.1021/jm701225u. PubMed DOI

Stetter H., Wulff C. Über Verbindungen mit Urotropin-Struktur, XXIV1) Derivative des 1-Amino-adamantans. Chem. Ber. 1962;95:2302–2304. doi: 10.1002/cber.19620950932. DOI

Munch H., Hansen J.S., Pittelkow M., Christensen J.B., Boas U. A new efficient synthesis of isothiocyanates from amines using di-tert-butyl dicarbonate. Tetrahedron Lett. 2008;49:3117–3119. doi: 10.1016/j.tetlet.2008.03.045. DOI

Ellman G.L., Courtney K.D., Andres V., Feather-Stone R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961;7:88–95. doi: 10.1016/0006-2952(61)90145-9. PubMed DOI

Pohanka M., Jun D., Kuca K. Improvement of acetylcholinesterase-based assay for organophosphates in way of identification by reactivators. Talanta. 2008;77:451–454. doi: 10.1016/j.talanta.2008.06.007. PubMed DOI

Greig N.H., Utsuki T., Yu Q., Zhu X., Holloway H.W., Perry T., Lee B., Ingram D.K., Lahiri D.K. A new therapeutic target in Alzheimer’s disease treatment: Attention to butyrylcholinesterase. Curr. Med. Res. Opin. 2001;17:159–165. PubMed

Harel M., Schalk I., Ehret-Sabatier L., Bouet F., Goeldner M., Hirth C., Axelsen P.H., Silman I., Sussman J.L. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. USA. 1993;90:9031–9035. PubMed PMC

Rydberg E.H., Brumshtein B., Greenblatt H.M., Wong D.M., Shaya D., Williams L.D., Carlier P.R., Pang Y.P., Silman I., Sussman J.L. Complexes of alkylene-liked tacrine dimers with Torpedo california acetylcholinesterase: Binding of Bis(5)-tacrine produces a dramatic rearrangement in the active-site gorge. J. Med. Chem. 2006;49:5491–5500. PubMed

Camps P., Formosa X., Galdeano C., Munoz-Torrero D., Ramirez L., Gomez E., Isambert N., Lavilla R., Badia A., Clos M.V., et al. Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. J. Med. Chem. 2009;52:5365–5379. PubMed

Fernandez-Bachiller M.I., Perez C., Campillo N.E., Paez J.A., Gonzales-Munoz G.C., Usan P., Garcia-Palomero E., Lopez M.G., Villarroya M., Garcia A.G., et al. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer’s disease, with cholinergic, antioxidant, and neuroprotective properties. ChemMedChem. 2009;4:828–841. doi: 10.1002/cmdc.200800414. PubMed DOI

Haviv H., Wong D.M., Greenblatt H.M., Carlier P.R., Pang Y.P., Silman I., Sussman J.L. Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase. J. Am. Chem. Soc. 2005;127:11029–11036. PubMed

Nicolet Y., Lockbridge O., Masson P., Fontecilla-Camps J.C., Nachon F. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. J. Biol. Chem. 2003;278:41141–41147. PubMed

Trott O., Olson A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010;31:455–461. PubMed PMC

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. PubMed

Kryger G., Harel M., Giles K., Toker L., Velan B., Lazar A., Kronman C., Barak D., Ariel N., Shafferman A., et al. Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr. D Biol. Crystalogr. 2000;56:1385–1394. doi: 10.1107/S0907444900010659. PubMed DOI

DeLano W.L. The PyMOL Molecular Graphics System. [(accessed on 1 January 2002)]. Available online: http://www.pymol.org.

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