Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.

CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 62500 Brno Czech Republic

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 61242 Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 61242 Brno Czech Republic

Facultad de Química Bioquímica y Farmacia Universidad Nacional de San Luis IMIBIO SL CONICET Chacabuco 915 San Luis 5700 Argentina

Global Change Research Institute CAS Belidla 986 4a 60300 Brno Czech Republic

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World Health Organization (WHO) Dementia. [(accessed on 24 August 2017)]; Available online: http://www.who.int/mediacentre/factsheets/fs362/en/

Pisani L., Farina R., Catto M., Iacobazzi R.M., Nicolotti O., Cellamare S., Mangiatordi G.F., Denora Nunzio S.R., Siragusa L., Altomare C.D., et al. Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents. J. Med. Chem. 2016;59:6791–6806. doi: 10.1021/acs.jmedchem.6b00562. PubMed DOI

Reitz Ch., Brayne C., Mayeux R. Epidemiology of Alzheimer disease. Nat. Rev. Neurol. 2011;7:137–152. doi: 10.1038/nrneurol.2011.2. PubMed DOI PMC

Novak P., Schmidt R., Kontsekova E., Zilka N., Kovacech B., Skrabana R., Vince-Kazmerova Z., Katina S., Fialova L., Prcina M., et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: A randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16 doi: 10.1016/S1474-4422(16)30331-3. PubMed DOI

Wang D.-M., Feng B., Fu H., Liu A.L., Wang L., Du G.H., Wu S. Design, Synthesis, and Biological Evaluation of a New Series of Biphenyl/Bibenzyl Derivatives Functioning as Dual Inhibitors of Acetylcholinesterase and Butyrylcholinesterase. Molecules. 2017;22:172. doi: 10.3390/molecules22101658. PubMed DOI PMC

De Oliveira J.S., Husein A.F., Lopes D.G., Adeniyi A.S., Vidal P.T., Signor C., Da Silva B.J., Baldissarelli J., Suéling L.L., Pereira M.R., et al. Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death. NeuroToxicology. 2016;57:241–250. doi: 10.1016/j.neuro.2016.10.008. PubMed DOI

Dvir H., Silman I., Harel M., Rossenbery T., Sussman J. Acetylcholinesterase: From 3D structure to function. Chem.-Biol. Interact. 2010;187:10–22. doi: 10.1016/j.cbi.2010.01.042. PubMed DOI PMC

Padrtova T., Marvanova P., Mokry P. Quaternary Ammonium Salts—Synthesis and Use. Chem. Listy. 2017;111:197–205.

Mokry P., Zemanova M., Csöllei J., Racanska E., Tumova I. Synthesis and pharmacological evaluation of novel potential ultrashort-acting β-blockers. Pharmazie. 2003;58:18–21. PubMed

Connors S.P., Dennis P.D., Gill E.W., Terrar D.A. The Synthesis and Potassium Channel Blocking Activity of some (4-Methanesulfonamidophenoxy)propanolamines as Potential Class III Antiarrhythmic Agents. J. Med. Chem. 1991;34:1570–1577. doi: 10.1021/jm00109a007. PubMed DOI

Acevedo O., Jorgensen W.L. Exploring Solvent Effects upon the Menshutkin Reaction Using a Polarizable Force Field. J. Phys. Chem. 2010;114:8425–8430. doi: 10.1021/jp100765v. PubMed DOI PMC

Fan P., Terrier L., Hay A.-E., Marston A., Hosttetmann K. Antioxidant and enzyme inhibition activities and chemical profiles of Polygonum sachalinensis F.Schmidt ex Maxim (Polygonaceae) Fitoterapia. 2010;81:124–131. doi: 10.1016/j.fitote.2009.08.019. PubMed DOI

Xie Q., Zheng Z., Shao B., Fu W., Xia Z., Li W., Sun J., Zheng W., Zhang W., Sheng W., et al. Pharmacophore-based design and discovery of (−)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis. J. Enzym. Inhib. Med. Chem. 2017;32:659–671. doi: 10.1080/14756366.2016.1265521. PubMed DOI PMC

Morris G., Huey R., Lindstrom W., Sanner M., Belew R., Goodsell D., Olson A. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009;30:2785–2791. doi: 10.1002/jcc.21256. PubMed DOI PMC

Case D.A., Darden T.A., Cheatham T.E., III, Simmerling C.L., Wang J., Duke R.E., Luo R., Walker R.C., Zhang W., Merz K.M., et al. AMBER 12 OR. University of California; San Francisco, CA, USA: 2012.

Bader R. Atoms in Molecules: A Quantum Theory. Oxford University Press; Oxford, UK: 1994.

Graham L.P. An Introduction to Medicinal Chemistry. Oxford University Press; Oxford, UK: 2009. pp. 599–604. Chapter 22.

Andujar S., Tosso R., Suvire F., Angelina E., Peruchena N., Cabedo N., Cortes D., Enriz D. Searching the “Biologically Relevant” Conformation of dopamine: A computational approach. J. Chem. Inf. Model. 2012;52:99–112. doi: 10.1021/ci2004225. PubMed DOI

Tosso Rodrigo D., Andujar S.A., Gutierrez L., Angelina E., Rodríguez R., Nogueras M., Baldoni H., Suvire F.D., Cobo J., Enriz D. Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J. Chem. Inf. Model. 2013;53:2018–2032. doi: 10.1021/ci400178h. PubMed DOI

Párraga J., Cabedo N., Andujar S., Piqueras L., Moreno L., Galán A., Angelina E., Enriz D., Ivorra M.D., Sanz M.J., et al. 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur. J. Med. Chem. 2013;68:150–166. doi: 10.1016/j.ejmech.2013.07.036. PubMed DOI

Angelina E., Andujar S., Tosso R., Enriz D., Peruchena N. Non-covalent interactions in receptor-ligand complexes. A study based on the electron charge density. J. Phys. Org. Chem. 2014;27:128–134. doi: 10.1002/poc.3250. DOI

Párraga J., Andujar S.A., Rojas S., Gutierrez L.J., El Aouad N., Sanz M.J., Enriz D., Cabedo N., Cortes D. Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands. Eur. J. Med. Chem. 2016;122:27–42. doi: 10.1016/j.ejmech.2016.06.009. PubMed DOI

Bar-On P., Millard C.B., Harel M., Dvir H., Enz A., Sussman J.L., Silman I. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002;41:3555–3564. doi: 10.1021/bi020016x. PubMed DOI

Wilson I., Hatch M.A., Ginsburg S. Carbamylation of acetylcholinesterase. J. Biol. Chem. 1960;235:2312–2315. PubMed

Wilson I., Harrison M.A., Ginsburg S. Carbamyl Derivatives of Acetylcholinesterase. J. Biol. Chem. 1961;236:1498–1500. PubMed

Deák K., Takács-Novák K., Kapás M., Vastag M., Tihanyi K., Noszál B. Physico-chemical characterization of a novel group of dopamine D3/D2 receptor ligands, potential atypical antipsychotic agents. J. Pharm. Biomed. Anal. 2008;48:678–684. doi: 10.1016/j.jpba.2008.06.021. PubMed DOI

Giaginis C., Tsantilli-Kakoulidou A. current state of the art in HPLC methodology for lipophilicity assessment of basic drugs. A review. J. Liquid Chromatogr. Relat. Technol. 2007;31:79–96. doi: 10.1080/10826070701665626. DOI

Lombardo F., Shalaeva M., Bissett B., Chistokhodova N. Physicochemical and biological profiling in drug research. ElogD7.4 20,000 compounds later: Refinements, observations, and applications. Pharmacokinet. Profil. Drug Res. 2006;187 doi: 10.1002/9783906390468.ch12. DOI

Poole S.K., Patel S., Dehring K., Workman H., Poole C.F. Determination of acid dissociation constants by capillary electrophoresis. J. Chromatogr. A. 2004;1037:445–454. doi: 10.1016/j.chroma.2004.02.087. PubMed DOI

Nowak P., Woźniakiewicz M., Kościelniak P. Application of capillary electrophoresis in determination of acid dissociation constant values. J. Chromatogr. A. 2015;1377:1–12. doi: 10.1016/j.chroma.2014.12.032. PubMed DOI

Andrasi M., Buglyo P., Zekany L., Gaspar A. A comparative study of capillary zone electrophoresis and pH-potentiometry for determination of dissociation constants. J. Pharm. Biomed. Anal. 2007;44:1040–1047. doi: 10.1016/j.jpba.2007.04.024. PubMed DOI

Tengler J., Kapustikova I., Pesko M., Govender R., Keltosova S., Mokrý P., Kollár P., O´Mahony J., Coffey A., Kráĺová K., et al. Synthesis and biological evaluation of 2-Hydroxy-3-[(2-aryloxyethyl)amino]propyl 4-[(Alkoxycarbonyl)amino]benzoates. Sci. World J. 2013 doi: 10.1155/2013/274570. PubMed DOI PMC

Luan F., Ma W., Zhang H., Zhang X., Liu M., Hu Z., Fan B. Prediction of pKa for neutral and basic drugs based on radial basis function neural networks and the heuristic method. Pharm. Res. 2005;9:1454–1460. doi: 10.1007/s11095-005-6246-8. PubMed DOI

Chemical Production Division Environmental Stewardship Branch; Canada: 2014. [(accessed on 25 August 2017)]. Reference Method for Measuring the Surface Tension of Chromium Electroplating, Chromium Anodizing and Reverse Etching Solutions with a Stalagmometer. Available online: https://www.ec.gc.ca/lcpe-cepa/E4899604-74FB-46D1-8E41-E3E24D6A7916/Methode-Reference-Method-eng.pdf.

Greenblatt H.M., Kryger G., Lewis T., Silman I., Sussman J.L. Structure of acetylcholinesterase complexed with (−)-galanthamine at 2.3 Å resolution. FEBS Lett. 1999;463:321–326. doi: 10.1016/S0014-5793(99)01637-3. PubMed DOI

Lindorff-Larsen K., Piana S., Palmo K., Maragakis P., Klepeis J., Dror R., Shaw D. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins Struct. Funct. Bioinform. 2010 doi: 10.1002/prot.22711. PubMed DOI PMC

Wang J., Wolf R., Caldwell J., Kollman P., Case D. Development and testing of a general amber force field. J. Comput. Chem. 2004;25:1157–1174. doi: 10.1002/jcc.20035. PubMed DOI

Jorgensen W., Chandrasekhar J., Madura J., Impey R., Klein M. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983;79:926–935. doi: 10.1063/1.445869. DOI

Essmann U., Perera L., Berkowitz M., Darden T., Lee H., Pedersen L. A smooth particle mesh Ewald method. J. Chem. Phys. 1995;103:8577–8593. doi: 10.1063/1.470117. DOI

Ryckaert J.-P., Ciccotti G., Berendsen H. Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J. Comput. Phys. 1977;23:327–341. doi: 10.1016/0021-9991(77)90098-5. DOI

Izaguirre J., Catarello D., Wozniak J., Skeel R. Langevin stabilization of molecular dynamics. J. Chem. Phys. 2001;114:2090–2098. doi: 10.1063/1.1332996. DOI

The PyMOL Molecular Graphics System, Version 1.8. Schrödinger, LLC; New York, NY, USA: 2015.

Lu T., Chen F. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 2012;33:580–592. doi: 10.1002/jcc.22885. PubMed DOI

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation