Palladium (II)-N-heterocyclic Carbene Complexes: Synthesis, Molecular
Docking, UV-Vis Absorption and Enzyme Inhibition

Sofiane      ikhlef; Sarra      Lasmari; El Hassen      Mokrani; Raouf      Boulcina; Chawki      Bensouici; Nevin      Gürbüz; Ismail      Özdemir

doi:10.2174/1570180820666230508154948

Abstract

Background: Alzheimer's disease is the most prevalent form of dementia; it affects the brain regions responsible for thought, memory, and language. Dementia cannot currently be cured by any medication.

Objective: We aimed to synthesize Pd-NHC type PEPPSI and investigate their biological activity in anticholinesterase enzymes.

Methods: In this study, we described preparing a series of Pd-NHC type PEPPSI obtained from their unsymmetrical benzimidazolium salts. These complexes (3a-f) were synthesized from the 2- chloromethyl-1,3-dioxalane benzimidazolium salts, PdCl2, KBr and pyridine. The compounds (3a-f) were tested against two enzymes (AChE and BChE).

Results: The results showed that most of the Palladium–NHC complexes effectively inhibited AChE with IC₅₀values in the range of 4.94 - 40.03 μM, and for BChE are in the range of 4.21 - 21.28 μM. The results showed that the compound (3a) was the most potent inhibitor activity against both AChE and BChE. The inhibition parameter (IC₅₀) was calculated by the spectrophotometric method. The inhibitory effects of the synthesized Pd-NHCs were compared to galantamine as a clinical cholinergic enzyme inhibitor. Additionally, Molecular docking is carried out to estimate the binding pattern between the newly synthesized compounds and both AChE and BChE active sites.

Conclusion: The results demonstrated that all synthesized compounds show excellent to moderate inhibition against the examined enzymes (AChE/BChE).

« Previous Next »

[1]
Yeong, K.Y.; Liew, W-L.; Murugaiyah, V.; Ang, C.W.; Osman, H.; Tan, S.C. Ethyl nitrobenzoate: A novel scaffold for cholinesterase inhibition. Bioorg. Chem.,  2017, 70, 27-33.
 [http://dx.doi.org/10.1016/j.bioorg.2016.11.005]

[2]
Kamal, M.A.; Klein, P.; Yu, Q.; Tweedie, D.; Li, Y.; Holloway, H.W.; Greig, N.H. Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine. J. Alzheimers Dis.,  2006, 10(1), 43-51.
 [http://dx.doi.org/10.3233/JAD-2006-10108] [PMID:  16988481]

[3]
Muñoz-Torrero, D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer’s disease. Curr. Med. Chem.,  2008, 15(24), 2433-2455.
 [http://dx.doi.org/10.2174/092986708785909067] [PMID:  18855672]

[4]
Özgeriş, B.; Göksu, S.; Polat Köse, L.; Gülçin, İ.; Salmas, R.E.; Durdagi, S.; Tümer, F.; Supuran, C.T. Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin scaffolds. Bioorg. Med. Chem.,  2016, 24(10), 2318-2329.
 [http://dx.doi.org/10.1016/j.bmc.2016.04.002] [PMID:  27068142]

[5]
Orhan, g.; Orhan, I; Sener, B. Recent developments in natural and synthetic drug research for Alzheimer’s Disease. Lett. Drug Des. Discov.,  2006, 3(4), 268-274.
 [http://dx.doi.org/10.2174/157018006776743215]

[6]
Khan, S.; Tariq, M.; Ashraf, M.; Abdullah, S.; Rashida, M.; Khalid, M.; Taslimi, P.; Fatima, M.; Zafar, R.; Shafiq, Z. 2-acetylbenzofuran hydrazones and their metal complexes as α-glucosidase inhibitors. Bioorg. Chem.,  2020, 102, 104082.
 [http://dx.doi.org/10.1016/j.bioorg.2020.104082]

[7]
Huseynova, A.; Kaya, R.; Taslimi, P.; Farzaliyev, V.; Mammadyarova, X.; Sujayev, A.; Tüzün, B.; Kocyigit, U.M.; Alwasel, S.; Gulçin, İ. Design, synthesis, characterization, biological evaluation, and molecular docking studies of novel 1,2-aminopropanthiols substituted derivatives as selective carbonic anhydrase, acetylcholinesterase and α-glycosidase enzymes inhibitors. J. Biomol. Struct. Dyn.,  2022, 40(1), 236-248.
 [http://dx.doi.org/10.1080/07391102.2020.1811772] [PMID:  32851915]

[8]
Massoulié, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette, F.M. Molecular and cellular biology of cholinesterases. Prog. Neurobiol.,  1993, 41(1), 31-91.
 [http://dx.doi.org/10.1016/0301-0082(93)90040-Y] [PMID:  8321908]

[9]
Bursal, E.; Taslimi, P.; Gören, A.C.; Gülçin, I. Assessments of anticholinergic, antidiabetic, antioxidant activities and phenolic content of Stachys annua. Biocatal. Agric. Biotechnol.,  2020, 28, 101711.
 [http://dx.doi.org/10.1016/j.bcab.2020.101711]

[10]
Işık, M.; Akocak, S.; Lolak, N.; Taslimi, P.; Türkeş, C.; Gülçin, İ.; Durgun, M.; Beydemir, Ş. Synthesis, characterization, biological evaluation, and in silico studies of novel 1,3‐diaryltriazene‐substituted sulfathiazole derivatives. Arch. Pharm.,  2020, 353(9), 2000102.
 [http://dx.doi.org/10.1002/ardp.202000102]

[11]
Gocer, H.; Topal, F.; Topal, M.; Küçük, M.; Teke, D.; Gülçin, İ.; Alwasel, S.H.; Supuran, C.T. Acetylcholinesterase and carbonic anhydrase isoenzymes I and II inhibition profiles of taxifolin. J. Enzyme Inhib. Med. Chem.,  2015, 31(3), 1-7.
 [http://dx.doi.org/10.3109/14756366.2015.1036051] [PMID:  25893707]

[12]
Digiacomo, M.; Chen, Z.; Wang, S.; Lapucci, A.; Macchia, M.; Yang, X.; Chu, J.; Han, Y.; Pi, R.; Rapposelli, S. Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg. Med. Chem. Lett.,  2015, 25(4), 807-810.
 [http://dx.doi.org/10.1016/j.bmcl.2014.12.084] [PMID:  25597007]

[13]
Öfele, K. 1,3-Dimethyl-4-imidazolinyliden-(2)-pentacarbonylchrom ein neuer übergangsmetall-carben-komplex. J. Organomet. Chem.,  1968, 12(3), P42-P43.
 [http://dx.doi.org/10.1016/S0022-328X(00)88691-X]

[14]
Wanzlick, H-W.; Schönherr, H-J. Direct synthesis of a mercury salt-carbene complex. Angew. Chem. Int. Ed. Engl.,  1968, 7(2), 141-142.
 [http://dx.doi.org/10.1002/anie.196801412]

[15]
Arduengo, A.J., III; Harlow, R.L.; Kline, M. A stable crystalline carbene. J. Am. Chem. Soc.,  1991, 113(1), 361-363.
 [http://dx.doi.org/10.1021/ja00001a054]

[16]
Hahn, F.E.; Jahnke, M.C. Heterocyclic carbenes: synthesis and coordination chemistry. Angew. Chem. Int. Ed.,  2008, 47(17), 3122-3172.
 [http://dx.doi.org/10.1002/anie.200703883]

[17]
Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett.,  1975, 16(50), 4467-4470.
 [http://dx.doi.org/10.1016/S0040-4039(00)91094-3]

[18]
Erdemir, F.; Aktaş, A.; Barut Celepci, D.; Gök, Y. New (NHC)Pd(II)(PPh3) complexes: Synthesis, characterization, crystal structure and its application on Sonogashira and Mizoroki–Heck cross-coupling reactions. Chem. Pap.,  2020, 74(1), 99-112.
 [http://dx.doi.org/10.1007/s11696-019-00859-x]

[19]
Aktaş, A.; Akkoç, S.; Gök, Y. Palladium catalyzed Mizoroki–Heck and Suzuki–Miyaura reactions using naphthalenomethyl-substituted imidazolidin-2-ylidene ligands in aqueous media. J. Coord. Chem.,  2013, 66(16), 2901-2909.
 [http://dx.doi.org/10.1080/00958972.2013.819092]

[20]
Huang, R.; Shaughnessy, K.H. Water-soluble palladacycles as precursors to highly recyclable catalysts for the suzuki coupling of aryl bromides in aqueous solvents. Organometallics,  2006, 25(17), 4105-4112.
 [http://dx.doi.org/10.1021/om050940y]

[21]
Torun, L.; Liu, S.; Madras, B.K.; Meltzer, P.C. Synthesis of 3-(4-heteroaryl-phenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters. Tetrahedron Lett.,  2006, 47(4), 599-603.
 [http://dx.doi.org/10.1016/j.tetlet.2005.10.170]

[22]
Şahin, N.; Gürbüz, N.; Karabıyık, H.; Karabıyık, H.; Özdemir, İ. Arylation of heterocyclic compounds by benzimidazole-based N-heterocyclic carbene-palladium(II) complexes. J. Organomet. Chem.,  2020, 907, 121076.
 [http://dx.doi.org/10.1016/j.jorganchem.2019.121076]

[23]
Türker, F.; Bereket, I.; Barut Celepci, D.; Aktaş, A.; Gök, Y. New Pd-PEPPSI complexes bearing meta-cyanobenzyl-Substituted NHC: Synthesis, characterization, crystal structure and catalytic activity in direct CeH arylation of (Hetero)arenes with aryl bromides. J. Mol. Struct.,  2020, 1205, 127608.
 [http://dx.doi.org/10.1016/j.molstruc.2019.127608]

[24]
Medici, S.; Peana, M.; Crisponi, G.; Nurchi, V.M.; Lachowicz, J.I.; Remelli, M.; Zoroddu, M.A. Silver coordination compounds: A new horizon in medicine. Coord. Chem. Rev.,  2016, 327-328, 349-359.
 [http://dx.doi.org/10.1016/j.ccr.2016.05.015]

[25]
Garrison, J.C.; Tessier, C.A.; Youngs, W.J. Synthesis and crystallographic characterization of multi-donor N-heterocyclic carbene chelating ligands and their silver complexes: Potential use in pharmaceuticals. J. Organomet. Chem.,  2005, 690(24-25), 6008-6020.
 [http://dx.doi.org/10.1016/j.jorganchem.2005.07.102]

[26]
(a) Hopkinson, M.N.; Richter, C.; Schedler, M.; Glorius, F. An overview of N-heterocyclic carbenes. Nature,  2014, 510(7506), 485-496.
 [http://dx.doi.org/10.1038/nature13384] [PMID: 24965649]; 
(b) Poyatos, M.; Mata, J.A.; Peris, E. Complexes with poly(N-heterocyclic carbene) ligands: Structural features and catalytic applications. Chem. Rev.,  2009, 109(8), 3677-3707.
 [http://dx.doi.org/10.1021/cr800501s] [PMID:  19236010]

[27]
Danopoulos, A.A.; Simler, T.; Braunstein, P. N-heterocyclic carbene complexes of copper, nickel, and cobalt. Chem. Rev.,  2019, 119(6), 3730-3961.
 [http://dx.doi.org/10.1021/acs.chemrev.8b00505] [PMID:  30843688]

[28]
(a) Fortman, G.C.; Nolan, S.P. N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: A perfect union. Chem. Soc. Rev.,  2011, 40(10), 5151-5169.
 [http://dx.doi.org/10.1039/c1cs15088j] [PMID: 21731956]; 
(b) Glorius, F. N-Heterocyclic Carbenes in Catalysis-An Introduction. In:  Topics in Organometallic Chemistry; Springer: Cham, 2006; pp. 1-20.
 [http://dx.doi.org/10.1007/3418_2006_059]

[29]
Aktaş, A.; Celepci, D.B.; Gök, Y.; Aygün, M. 2-Hydroxyethyl-substituted (NHC)Pd(II)PPh3 complexes: synthesis, characterization, crystal structure and its application on sonogashira cross-coupling reactions in aqueous media. ChemistrySelect,  2018, 3(39), 10932-10937.
 [http://dx.doi.org/10.1002/slct.201802519]

[30]
Karaaslan, M.G.; Aktaş, A.; Gürses, C.; Gök, Y.; Ateş, B. Chemistry, structure, and biological roles of Au-NHC complexes as TrxR inhibitors. Bioorg. Chem.,  2020, 95, 103552.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103552]

[31]
Al Nasr, I.; Touj, N.; Koko, W.; Khan, T.; Özdemir, I.; Yaşar, S.; Hamdi, N. Biological activities of NHC–Pd(II) complexes based on benzimidazolylidene N-heterocyclic carbene (NHC) ligands bearing aryl substituents. Catalysts,  2020, 10(10), 1190.
 [http://dx.doi.org/10.3390/catal10101190]

[32]
Düşünceli, S.D.; Ayaz, D.; Üstün, E.; Günal, S.; Özdemir, N.; Dinçer, M.; Özdemir, İ. Synthesis, antimicrobial properties, and theoretical analysis of benzimidazole-2-ylidene silver(I) complexes. J. Coord. Chem.,  2020, 73(13), 1967-1986.
 [http://dx.doi.org/10.1080/00958972.2020.1812587]

[33]
Slimani, I.; Mansour, L.; Abutaha, N.; Harrath, A.H.; Al-Tamimi, J.; Gürbüz, N.; Özdemir, I.; Hamdi, N. Synthesis, structural characterization of silver(I)-NHC complexes and their antimicrobial, antioxidant and antitumor activities. J. King Saud Univ. Sci.,  2020, 32(2), 1544-1554.
 [http://dx.doi.org/10.1016/j.jksus.2019.12.010]

[34]
Hickey, J.L.; Ruhayel, R.A.; Barnard, P.J.; Baker, M.V.; Berners-Price, S.J.; Filipovska, A. Mitochondria-targeted chemotherapeutics: The rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J. Am. Chem. Soc.,  2008, 130(38), 12570-12571.
 [http://dx.doi.org/10.1021/ja804027j] [PMID:  18729360]

[35]
Mercs, L.; Albrecht, M. Beyond catalysis: N-heterocyclic carbene complexes as components for medicinal, luminescent, and functional materials applications. Chem. Soc. Rev.,  2010, 39(6), 1903-1912.
 [http://dx.doi.org/10.1039/b902238b] [PMID:  20502793]

[36]
Lasmari, S.; Gürbüz, N.; Boulcina, R.; Özdemir, N.; Özdemir, İ. Synthesis of [PdBr2(benzimidazole-2-ylidene)(pyridine)] complexes and their catalytic activity in the direct C H bond activation of 2-substituted heterocycles. Polyhedron,  2021, 199, 115091.
 [http://dx.doi.org/10.1016/j.poly.2021.115091]

[37]
Lasmari, S.; Ikhlef, S.; Boulcina, R.; Mokrani, E.H.; Bensouici, C.; Gürbüz, N.; Dündar, M.; Karcı, H.; Özdemir, İ.; Koç, A.; Özdemir, I.; Debache, A. New silver Nheterocyclic carbenes complexes: Synthesis, molecular docking study and biological activities evaluation as cholinesterase inhibitors and antimicrobials. J. Mol. Struct.,  2021, 1238, 130399.
 [http://dx.doi.org/10.1016/j.molstruc.2021.130399]

[38]
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]

[39]
Release, S. 2015-1: Maestro, version 10.1; Schrodinger, LLC: New York, 2015. 

[40]
Sandeli, A.E.K.; Khiri-Meribout, N.; Benzerka, S.; Gürbüz, N.; Dündar, M.; Karcı, H.; Bensouici, C.; Mokrani, E.H.; Özdemir, İ.; Koç, A.; Özdemir, N.; Debache, A.; Özdemir, İ. Silver (I)-N-heterocyclic carbene complexes: Synthesis and characterization, biological evaluation of Anti-Cholinesterase, anti-alpha-amylase, anti-lipase, and antibacterial activities, and molecular docking study. Inorg. Chim. Acta,  2021, 525, 120486.
 [http://dx.doi.org/10.1016/j.ica.2021.120486]

[41]
Demmak, R.G.; Bordage, S.; Bensegueni, A.; Boutaghane, N.; Hennebelle, T.; Mokrani, E.H.; Sahpaz, S. Chemical constituents from Solenostemma argel and their cholinesterase inhibitory activity. Nat. Prod. Sci.,  2019, 25(2), 115-121.
 [http://dx.doi.org/10.20307/nps.2019.25.2.115]

[42]
Mokrani, E.H.; Abdelaziz, M.A.; Akakba, N.; Teniou, S.; Demmam, R.G.; Bensegueni, A. Identification of new potent Tubulin Colchicine Binding Site inhibitors for potential antitumor drug using molecular docking and drug-likeness prediction. Cumhuriyet Science Journal.,  2022, 43(3), 398-403.
 [http://dx.doi.org/10.17776/csj.1063966]

[43]
Jones, G.; Willett, P.; Glen, R.C. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J. Mol. Biol.,  1995, 245(1), 43-53.
 [http://dx.doi.org/10.1016/S0022-2836(95)80037-9] [PMID:  7823319]

[44]
The PyMOL Molecular Graphics System Version 2.2.3.  Available From: https://pymol.org

[45]
Ruiz-Botella, S.; Peris, E. Phenylene- and Biphenylene-Bridged Bis-Imidazolylidenes of Palladium. Organometallics,  2014, 33(19), 5509-5516.
 [http://dx.doi.org/10.1021/om500765u]

[46]
Wang, H.M.J.; Lin, I.J.B. Facile synthesis of silver(i)−carbene complexes. Useful carbene transfer agents. Organometallics,  1998, 17(5), 972-975.
 [http://dx.doi.org/10.1021/om9709704]

[47]
Kaloğlu, N.; Özdemir, İ.; Günal, S.; Özdemir, İ. Synthesis and antimicrobial activity of bulky 3,5‐di‐ tert ‐butyl substituent‐containing silver–N‐heterocyclic carbene complexes. Appl. Organomet. Chem.,  2017, 31(11), e3803.
 [http://dx.doi.org/10.1002/aoc.3803]

[48]
Akkoç, S.; Gök, Y.; İlhan, İ.Ö.; Kayser, V. N -Methylphthalimide-substituted benzimidazolium salts and PEPPSI Pd–NHC complexes: Synthesis, characterization and catalytic activity in carbon–carbon bond-forming reactions. Beilstein J. Org. Chem.,  2016, 12, 81-88.
 [http://dx.doi.org/10.3762/bjoc.12.9] [PMID:  26877810]

[49]
Graham, B.; Fayter, A.E.R.; Gibson, M.I. Synthesis of anthracene conjugates of truncated antifreeze protein sequences: effect of the end group and photocontrolled dimerization on ice recrystallization inhibition activity. Biomacromolecules,  2019, 20(12), 4611-4621.
 [http://dx.doi.org/10.1021/acs.biomac.9b01538] [PMID:  31714763]

[50]
Arıcı, H.; Sündü, B.; Fırıncı, R.; Ertuğrul, E.; Özdemir, N.; Çetinkaya, B.; Metin, Ö.; Günay, M.E. The synthesis of new PEPPSI-type N-heterocyclic carbene (NHC)-Pd(II) complexes bearing long alkyl chain as precursors for the synthesis of NHC-stabilized Pd(0) nanoparticles and their catalytic applications. J. Organomet. Chem.,  2021, 934, 121633.
 [http://dx.doi.org/10.1016/j.jorganchem.2020.121633]

[51]
Yamali, C.; Gül, H.I.; Ece, A. Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes. Chem. Biol. Drug Des.,  2018, 91(4), 854-866.

[52]
Mokrani, E.H.; Bensegueni, A.; Chaput, L.; Beauvineau, C.; Djeghim, H.; Mouawad, L. identification of new potent acetylcholinesterase inhibitors using virtual screening and in vitro approaches. Mol. Inform.,  2019, 38(5), 1800118.
 [http://dx.doi.org/10.1002/minf.201800118] [PMID:  30725535]

Rights & Permissions Print Cite

Explore Articles

Open Access

Open Access Articles

DOI https://dx.doi.org/10.2174/1570180820666230508154948	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

Palladium (II)-N-heterocyclic Carbene Complexes: Synthesis, Molecular Docking, UV-Vis Absorption and Enzyme Inhibition

Abstract Play Pause

Abstract