Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

Biomedical Research Centre and Department of Neurology University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Kralove Charles University Prague Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Hradec Kralove Czech Republic

Faculty of Medicine in Hradec Kralove Charles University Prague Hradec Kralove Czech Republic

Institute of General Organic Chemistry Laboratory of Medicinal Chemistry Madrid Spain

See more in PubMed

Prince M, Ali G-C, Guerchet M, et al. . Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 2016;8:23. 10.1186/s13195-016-0188-8. PubMed DOI PMC

Lane CA, Hardy J, Schott JM.. Alzheimer’s disease. Eur J Neurol 2018;25:59–70. 10.1111/ene.13439. PubMed DOI

Zemek F, Drtinova L, Nepovimova E, et al. . Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf 2014;13:759–74. 10.1517/14740338.2014.914168. PubMed DOI

Grossberg GT, Manes F, Allegri RF, et al. . The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs 2013;27:469–78. 10.1007/s40263-013-0077-7. PubMed DOI PMC

Weller J, Budson A.. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Res 2018;7:1161. 10.12688/f1000research.14506.1. PubMed DOI PMC

Cummings JL. The impact of depressive symptoms on patients with Alzheimer disease. Alzheimer Dis Assoc Disord 2003;17:61–2. 10.1097/00002093-200304000-00001. PubMed DOI

Lyketsos CG, Lopez O, Jones B, et al. . Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002;288:1475–83. 10.1001/jama.288.12.1475. PubMed DOI

Starkstein SE, Mizrahi R.. Depression in Alzheimer’s disease. Expert Rev Neurother 2006;6:887–95. 10.1586/14737175.6.6.887. PubMed DOI

Tipton KF. 90 years of monoamine oxidase: some progress and some confusion. J Neural Transm (Vienna) 2018;125:1519–51. 10.1007/s00702-018-1881-5. PubMed DOI

Nicotra A, Pierucci F, Parvez H, Senatori O.. Monoamine oxidase expression during development and aging. Neurotoxicology 2004;25:155–65. 10.1016/S0161-813X(03)00095-0. PubMed DOI

Ramsay RR. Molecular aspects of monoamine oxidase B. Prog Neuropsychopharmacol Biol Psychiatry 2016;69:81–9. 10.1016/j.pnpbp.2016.02.005. PubMed DOI

Bautista-Aguilera ÓM, Hagenow S, Palomino-Antolin A, et al. . Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases. Angewandte Chem Int Ed 2017;56:12765–9. 10.1002/anie.201706072. PubMed DOI

Bautista-Aguilera ÓM, Budni J, Mina F, et al. . Contilisant, a tetratarget small molecule for Alzheimer’s disease therapy combining cholinesterase, monoamine oxidase inhibition, and H3R antagonism with S1R agonism profile. J Med Chem 2018;61:6937–43. 10.1021/acs.jmedchem.8b00848. PubMed DOI

Weinreb O, Amit T, Bar-Am O, Youdim MBH.. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr Drug Targets 2012;13:483–94. 10.2174/138945012799499794. PubMed DOI

Weinstock M, Bejar C, Wang RH, et al. . TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease. J Neural Transm Suppl 2000;60:157–69. 10.1007/978-3-7091-6301-6_10. PubMed DOI

Weinstock M, Gorodetsky E, Poltyrev T, et al. . A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:555–61. 10.1016/S0278-5846(03)00053-8. PubMed DOI

Weinreb O, Amit T, Bar-Am O, Youdim MBH.. A novel anti-Alzheimer’s disease drug, ladostigil neuroprotective, multimodal brain-selective monoamine oxidase and cholinesterase inhibitor. Int Rev Neurobiol 2011;100:191–215. 10.1016/B978-0-12-386467-3.00010-8. PubMed DOI

Sagi Y, Weinstock M, Youdim MBH.. Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. J Neurochem 2003;86:290–7. 10.1046/j.1471-4159.2003.01801.x. PubMed DOI

Korábečný J, Nepovimová E, Cikánková T, et al. . Newly developed drugs for Alzheimer’s disease in relation to energy metabolism, cholinergic and monoaminergic neurotransmission. Neuroscience 2018;370:191–206. 10.1016/j.neuroscience.2017.06.034. PubMed DOI

León R, Garcia AG, Marco-Contelles J.. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 2013;33:139–89. 10.1002/med.20248. PubMed DOI

Gallagher DA, Schrag, A.. Impact of newer pharmacological treatments on quality of life in patients with Parkinson’s disease. CNS Drugs 2008;22:563–86. 10.2165/00023210-200822070-00003. PubMed DOI

do Carmo Carreiras M, Ismaili L, Marco-Contelles J.. Propargylamine-derived multi-target directed ligands for Alzheimer’s disease therapy. Bioorg Med Chem Lett 2020;30:126880. 10.1016/j.bmcl.2019.126880. PubMed DOI

Youdim MB, Gross A, Finberg JP.. Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 2001;132:500–6. 10.1038/sj.bjp.0703826. PubMed DOI PMC

Weinreb O, Amit T, Bar-Am O, et al. . Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. J Neural Transm Suppl 2006;70:457–65. PubMed

Horak M, Holubova K, Nepovimova E, et al. . The pharmacology of tacrine at N-methyl-d-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry 2017;75:54–62. 10.1016/j.pnpbp.2017.01.003. PubMed DOI

Recanatini M, Cavalli A, Belluti F, et al. . SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J Med Chem 2000;43:2007–18. 10.1021/jm990971t. PubMed DOI

Kaniakova M, Korabecny J, Holubova K, et al. . 7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo. Biochem Pharmacol 2021;186:114460. 10.1016/j.bcp.2021.114460. PubMed DOI

Soukup O, Jun D, Zdarova-Karasova J, et al. . A resurrection of 7-MEOTA: a comparison with tacrine. Curr Alzheimer Res 2013;10:893–906. PubMed

Mao F, Li J, Wei H, et al. . Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer’s disease. J Enzyme Inhib Med Chem 2015;30:995–1001. 10.3109/14756366.2014.1003212. PubMed DOI

Tang J, Li J, Zhang L, et al. . The divergent transformations of aromatic o-aminonitrile with carbonyl compound. J Heterocyclic Chem 2012;49:533–42. 10.1002/jhet.804. DOI

Del Giudice MR, Borioni A, Mustazza C, et al. . Synthesis and cholinesterase inhibitory activity of 6-, 7-methoxy-(and hydroxy-) tacrine derivatives. Farmaco 1996;51:693–8. PubMed

Szymanski P, Karpiński A, Mikiciuk-Olasik E.. Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors. Eur J Med Chem 2011;46:3250–7. 10.1016/j.ejmech.2011.04.038. PubMed DOI

Spilovska K, Korabecny J, Kral J, et al. . 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer’s disease treatment–synthesis, biological evaluation and molecular modeling studies. Molecules 2013;18:2397–418. 10.3390/molecules18022397. PubMed DOI PMC

Spilovska K, Korabecny J, Sepsova V, et al. . Novel tacrine-scutellarin hybrids as multipotent anti-alzheimer’s agents: design, synthesis and biological evaluation. Molecules 2017;22:1006. 10.3390/molecules22061006. PubMed DOI PMC

Ellman GL, Courtney KD, Andres V, Feather-Stone RM.. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol 1961;7:88–95. 10.1016/0006-2952(61)90145-9. PubMed DOI

Lockridge O. Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses. Pharmacol Ther 2015;148:34–46. 10.1016/j.pharmthera.2014.11.011. PubMed DOI

Greig NH, Lahiri DK, Sambamurti K.. Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. Int Psychogeriatr 2002;14:77–91. 10.1017/s1041610203008676. PubMed DOI

Nordberg A, Ballard C, Bullock R, et al. . A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease. Prim Care Companion CNS Disord 2013;15:PCC.12r01412. 10.4088/PCC.12r01412. PubMed DOI PMC

Inestrosa NC, Alvarez A, Pérez CA, et al. . Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 1996;16:881–91. 10.1016/s0896-6273(00)80108-7. PubMed DOI

Barak D, Ordentlich A, Kaplan D, et al. . Lessons from functional analysis of AChE covalent and noncovalent inhibitors for design of AD therapeutic agents. Chem Biol Interact 2005;157–158:219–26. 10.1016/j.cbi.2005.10.030. PubMed DOI

Zhang C, Lv Y, Bai R, Xie Y.. Structural exploration of multifunctional monoamine oxidase B inhibitors as potential drug candidates against Alzheimer’s disease. Bioorg Chem 2021;114:105070. 10.1016/j.bioorg.2021.105070. PubMed DOI

Verma P, Truhlar DG.. Status and challenges of density functional theory. Trends Chem 2020;2:302–18. 10.1016/j.trechm.2020.02.005. DOI

Borštnar R, Repič M, Kržan M, et al. . Irreversible inhibition of monoamine oxidase B by the antiparkinsonian medicines rasagiline and selegiline: a computational study. Eur J Organic Chem 2011;2011:6419–33. 10.1002/ejoc.201100873. DOI

Di L, Kerns EH, Fan K, et al. . High throughput artificial membrane permeability assay for blood-brain barrier. Eur J Med Chem 2003;38:223–32. PubMed

Wang Q, Rager JD, Weinstein K, et al. . Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm 2005;288:349–59. 10.1016/j.ijpharm.2004.10.007. PubMed DOI

Parepally JMR, Mandula H, Smith QR.. Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen, and indomethacin. Pharm Res 2006;23:873–81. 10.1007/s11095-006-9905-5. PubMed DOI

Romero A, Cacabelos R, Oset-Gasque MJ, et al. . Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2013;23:1916–22. 10.1016/j.bmcl.2013.02.017. PubMed DOI

Gracon SI, Knapp MJ, Berghoff WG, et al. . Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis Assoc Disord 1998;12:93–101. 10.1097/00002093-199806000-00007. PubMed DOI

Watkins PB, Zimmerman HJ, Knapp MJ, et al. . Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994;271:992–8. PubMed

Nepovimova E, Korabecny J, Dolezal R, et al. . Tacrine-trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J Med Chem 2015;58:8985–9003. 10.1021/acs.jmedchem.5b01325. PubMed DOI

Lineweaver H, Burk D.. The determination of enzyme dissociation constants. J Am Chem Soc 1934;56:658–66. 10.1021/ja01318a036 (last accessed 9 Mar 2022]. DOI

Carpenter TS, Kirshner DA, Lau EY, et al. . A method to predict blood-brain barrier permeability of drug-like compounds using molecular dynamics simulations. Biophys J 2014;107:630–41. 10.1016/j.bpj.2014.06.024. PubMed DOI PMC

Muckova L, Pejchal J, Jost P, et al. . Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure. Drug Chem Toxicol 2019;42:252–6. 10.1080/01480545.2018.1432641. PubMed DOI