Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In Silico, In Vitro and In Vivo Assessment of Acetylcholinesterase Inhibitory Activity of Theobromine Derivatives Containing an Arylpiperazine Fragment

Author(s): Lily Andonova, Maya Georgieva*, Mariyana Atanasova, Iva Valkova, Irini Doytchinova, Rumyana Simeonova, Dimitrina Zheleva-Dimitrova and Alexander Zlatkov

Volume 20, Issue 10, 2023

Published on: 18 October, 2022

Page: [1645 - 1655] Pages: 11

DOI: 10.2174/1570180819666220827162711

Price: $65

Abstract

Background: In the current Alzheimer’s disease therapy as the preferred treatment are applied acetylcholinesterase inhibitors. Aiming to identify the active pharmacophores necessary for increased acetylcholinesterase inhibitory activity, some docking studies have been applied.

Methods: In silico docking evaluation of the binding modes, identification of acetylcholinesterase inhibitory activity in vitro through Ellman’s test and ITC protocol, and the in vivo effect. PAMPA evaluation of the GIT and BBB permeability.

Results: In the present study, two series previously synthesized in our laboratory, arylpiperazine derivatives of theobromine, were docked into the rhAChE active sites. Ellman’s test outlined molecules LA1 and LA7 as the most active, with IC50 of 0.708 and 0.299 μM, respectively. In the acute toxicity test, LA7 given intraperitoneally in mice showed moderate toxicity with LD50 of 87.5 mg/kg. The new compound, administered i.p. for 12 days at doses 2 mg/kg/day and 4 mg/kg/day, respectively, showed a pronounced acetylcholinesterase inhibitory activity in vivo.

Conclusion: The corresponding binding modes were identified, where the docking pose for the studied molecules depends on the protonated state of the nitrogen atom of the piperazine moiety. In the best scored pose for LA7, the xanthine moiety is bound into the catalytic active site (CAS) of acetylcholinesterase, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). For the evaluated selected structures, good permeability through the GIT and BBB assessed by PAMPA was also determined.

Keywords: Acetylcholinesterase, molecular docking, AChE inhibitors, Ellman’s test, ITC protocol, in vivo

« Previous Next »
Graphical Abstract

[1]
Sadashiva, C.T.; Narendra Sharath Chandra, J.N.; Ponnappa, K.C.; Veerabasappa Gowda, T.; Rangappa, K.S. Synthesis and efficacy of 1-[bis(4-fluorophenyl)-methyl]piperazine derivatives for acetylcholinesterase inhibition, as a stimulant of central cholinergic neurotransmission in Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2006, 16(15), 3932-3936.
[http://dx.doi.org/10.1016/j.bmcl.2006.05.030] [PMID: 16735118]
[2]
Barril, X.; Orozco, M.; Luque, F. Towards improved acetylcholinesterase inhibitors: A structural and computational approach. Mini Rev. Med. Chem., 2001, 1(3), 255-266.
[http://dx.doi.org/10.2174/1389557013406828] [PMID: 12369972]
[3]
Balasubramanian, A.S.; Bhanumathy, C.D. Noncholinergic functions of cholinesterases. FASEB J., 1993, 7(14), 1354-1358.
[http://dx.doi.org/10.1096/fasebj.7.14.8224608] [PMID: 8224608]
[4]
Bassil, N.; Grossberg, G.T. Novel regimens and delivery systems in the pharmacological treatment of Alzheimer’s disease. CNS Drugs, 2009, 23(4), 293-307.
[http://dx.doi.org/10.2165/00023210-200923040-00003] [PMID: 19374459]
[5]
Kosaraju, J.; Madhunapantula, S.V.; Chinni, S.; Khatwal, R.B.; Dubala, A.; Muthureddy Nataraj, S.K.; Basavan, D. Dipeptidyl peptidase-4 inhibition by Pterocarpus marsupium and Eugenia jambolana ameliorates streptozotocin induced Alzheimer’s disease. Behav. Brain Res., 2014, 267, 55-65.
[http://dx.doi.org/10.1016/j.bbr.2014.03.026] [PMID: 24667360]
[6]
Kelley, B.J.; Petersen, R.C. Alzheimer’s disease and mild cognitive impairment. Neurol. Clin., 2007, 25(3), 577-609, v.
[http://dx.doi.org/10.1016/j.ncl.2007.03.008] [PMID: 17659182]
[7]
Ballard, C.G. Advances in the treatment of Alzheimer’s disease: Benefits of dual cholinesterase inhibition. Eur. Neurol., 2002, 47(1), 64-70.
[http://dx.doi.org/10.1159/000047952] [PMID: 11803198]
[8]
Sugimoto, H.; Ogura, H.; Arai, Y.; Iimura, Y.; Yamanishi, Y. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn. J. Pharmacol., 2002, 89(1), 7-20.
[http://dx.doi.org/10.1254/jjp.89.7] [PMID: 12083745]
[9]
Wilkinson, D.; Murray, J. Galantamine: A randomized, double-blind, dose comparison in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry, 2001, 16(9), 852-857.
[http://dx.doi.org/10.1002/gps.409] [PMID: 11571763]
[10]
Huang, W.; Yu, H.; Sheng, R.; Li, J.; Hu, Y. Identification of pharmacophore model, synthesis and biological evaluation of N-phenyl-1-arylamide and N-phenylbenzenesulfonamide derivatives as BACE 1 inhibitors. Bioorg. Med. Chem., 2008, 16(24), 10190-10197.
[http://dx.doi.org/10.1016/j.bmc.2008.10.059] [PMID: 19013073]
[11]
Sheng, R.; Xu, Y.; Hu, C.; Zhang, J.; Lin, X.; Li, J.; Yang, B.; He, Q.; Hu, Y. Design, synthesis and AChE inhibitory activity of indanone and aurone derivatives. Eur. J. Med. Chem., 2009, 44(1), 7-17.
[http://dx.doi.org/10.1016/j.ejmech.2008.03.003] [PMID: 18436348]
[12]
Demir Özkay, Ü.; Can, Ö.D. Sağlık, B.N.; Acar Çevik, U.; Levent, S.; Özkay, Y.; Ilgın, S.; Atlı Ö. Design, synthesis, and AChE inhibitory activity of new benzothiazole–piperazines. Bioorg. Med. Chem. Lett., 2016, 26(22), 5387-5394.
[http://dx.doi.org/10.1016/j.bmcl.2016.10.041] [PMID: 27789142]
[13]
Andonova, L.; Zheleva-Dimitrova, D.; Georgieva, M.; Zlatkov, A. Synthesis and antioxidant activity of some 1-aryl/aralkyl piperazine derivatives with xanthine moiety at N4. Biotechnol. Biotechnol. Equip., 2014, 28(6), 1165-1171.
[http://dx.doi.org/10.1080/13102818.2014.979978] [PMID: 26019603]
[14]
Andonova, L.; Valkova, I.; Zheleva-Dimitrova, D.; Georgieva, M.; Momekov, G.; Zlatkov, A. Synthesis of new N1Arylpiperazine substituted xanthine derivatives and evaluation of their antioxidant and cytotoxic effects. Anticancer. Agents Med. Chem., 2019, 19(4), 528-537.
[http://dx.doi.org/10.2174/1871520619666190121155651] [PMID: 30666917]
[15]
Cheung, J.; Rudolph, M.J.; Burshteyn, F.; Cassidy, M.S.; Gary, E.N.; Love, J.; Franklin, M.C.; Height, J.J. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem., 2012, 55(22), 10282-10286.
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[16]
Atanasova, M.; Stavrakov, G.; Philipova, I.; Zheleva, D.; Yordanov, N.; Doytchinova, I. Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity. Bioorg. Med. Chem., 2015, 23(17), 5382-5389.
[http://dx.doi.org/10.1016/j.bmc.2015.07.058] [PMID: 26260334]
[17]
Hristova, M.; Atanasova, M.; Valkova, I.; Andonova, L.; Doytchinova, I.; Zlatkov, A. Molecular docking study on 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione as acetylcholinesterase inhibitor. CBU International Conference On Innovations In Science And Education Proceedings, 2018, pp. 898-903.
[http://dx.doi.org/ 10.12955/cbup.v6.1268]
[18]
Instruction Manual, PAMPA 2016.
[19]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Featherstone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7(2), 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[20]
Ortiz, J.; Berkov, S.; Pigni, N.; Theoduloz, C.; Roitman, G.; Tapia, A.; Bastida, J.; Feresin, G. Wild Argentinian Amaryllidaceae, a new renewable source of the acetylcholinesterase inhibitor galanthamine and other alkaloids. Molecules, 2012, 17(11), 13473-13482.
[http://dx.doi.org/10.3390/molecules171113473] [PMID: 23149565]
[21]
Güleç, Ö. Türkeş C.; Arslan, M.; Demir, Y.; Yeni, Y.; Hacımüftüoğlu, A.; Ereminsoy, E.; Küfrevioğlu, Ö.İ.; Beydemir, Ş. Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif. Mol. Divers., 2022.
[http://dx.doi.org/10.1007/s11030-022-10422-8] [PMID: 35397086]
[22]
Türkeş C.; Akocak, S.; Işık, M.; Lolak, N.; Taslimi, P.; Durgun, M.; Gülçin, İ.; Budak, Y.; Beydemir, Ş. Novel inhibitors with sulfamethazine backbone: Synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors. J. Biomol. Struct. Dyn., 2021, 1-13.
[http://dx.doi.org/10.1080/07391102.2021.1916599] [PMID: 33950796]
[23]
Askin, S.; Tahtaci, H. Türkeş C.; Demir, Y.; Ece, A.; Akalın Çiftçi, G.; Beydemir, Ş. Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors. Bioorg. Chem., 2021, 113105009
[http://dx.doi.org/10.1016/j.bioorg.2021.105009] [PMID: 34052739]
[24]
Yaşar, Ü.; Gönül, İ.; Türkeş C.; Demir, Y.; Beydemir, Ş. Transition-metal complexes of bidentate schiff-base ligands: In vitro and in silico evaluation as non-classical carbonic anhydrase and potential acetylcholinesterase inhibitors. ChemistrySelect, 2021, 6(29), 7278-7284.
[http://dx.doi.org/10.1002/slct.202102082]
[25]
Akocak, S.; Taslimi, P.; Lolak, N. Işık, M.; Durgun, M.; Budak, Y.; Türkeş C.; Gülçin, İ.; Beydemir, Ş;. Synthesis, characterization, and inhibition study of novel substituted phenylureido sulfaguanidine derivatives as α-glycosidase and cholinesterase inhibitors. Chem. Biodivers., 2021, 18(4)e2000958
[http://dx.doi.org/10.1002/cbdv.202000958] [PMID: 33620128]
[26]
Duff, M.R., Jr; Grubbs, J.; Howell, E.E. Isothermal titration calorimetry for measuring macromolecule-ligand affinity. J. Vis. Exp., 2011, (55), 2796.
[PMID: 21931288]
[27]
Chinedu, E.; Arome, D.; Ameh, F. A new method for determining acute toxicity in animal models. Toxicol. Int., 2013, 20(3), 224-226.
[http://dx.doi.org/10.4103/0971-6580.121674] [PMID: 24403732]
[28]
Eduviere, A.T.; Umukoro, S.; Aderibigbe, A.O.; Ajayi, A.M.; Adewole, F.A. Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice. Life Sci., 2015, 132, 20-26.
[http://dx.doi.org/10.1016/j.lfs.2015.04.007] [PMID: 25921767]
[29]
Sadigh-Eteghad, S.; Mahmoudi, J.; Babri, S.; Talebi, M. Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function. Acta Cir. Bras., 2015, 30(11), 736-742.
[http://dx.doi.org/10.1590/S0102-865020150110000003] [PMID: 26647792]
[30]
Lowry, O.; Rosebrough, N.; Farr, A.L.; Randall, R. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 1951, 193(1), 265-275.
[http://dx.doi.org/10.1016/S0021-9258(19)52451-6] [PMID: 14907713]
[31]
ACDLabs. ACD Inc.,
[32]
Draczkowski, P.; Tomaszuk, A.; Halczuk, P.; Strzemski, M.; Matosiuk, D.; Jozwiak, K. Determination of affinity and efficacy of acetylcholinesterase inhibitors using isothermal titration calorimetry. Biochim. Biophys. Acta, Gen. Subj., 2016, 1860(5), 967-974.
[http://dx.doi.org/10.1016/j.bbagen.2015.11.006] [PMID: 26586471]
[33]
Di, L.; Kerns, E.H. Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol., 2003, 7(3), 402-408.
[http://dx.doi.org/10.1016/S1367-5931(03)00055-3] [PMID: 12826129]
[34]
Kerns, E.; Di, L. Pharmaceutical profiling in drug discovery. Drug Discov. Today, 2003, 8(7), 316-323.
[http://dx.doi.org/10.1016/S1359-6446(03)02649-7] [PMID: 12654544]
[35]
Bujard, A.; Petit, C.; Carrupt, P.A.; Rudaz, S.; Schappler, J. HDM-PAMPA to predict gastrointestinal absorption, binding percentage, equilibrium and kinetics constants with human serum albumin and using 2 end-point measurements. Eur. J. Pharm. Sci., 2017, 97, 143-150.
[http://dx.doi.org/10.1016/j.ejps.2016.11.001] [PMID: 27816629]
[36]
Doytchinova, I.; Atanasova, M.; Valkova, I.; Stavrakov, G.; Philipova, I.; Zhivkova, Z.; Zheleva-Dimitrova, D.; Konstantinov, S.; Dimitrov, I. Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 768-776.
[http://dx.doi.org/10.1080/14756366.2018.1458031] [PMID: 29651876]
[37]
Stavrakov, G.; Philipova, I.; Zheleva-Dimitrova, D.; Valkova, I.; Salamanova, E.; Konstantinov, S.; Doytchinova, I. Docking-based design and synthesis of galantamine-camphane hybrids as inhibitors of acetylcholinesterase. Chem. Biol. Drug Des., 2017, 90(5), 709-718.
[http://dx.doi.org/10.1111/cbdd.12991] [PMID: 28374576]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy