Abstract
Alzheimer’s disease is a degenerative brain condition that is the leading cause of dementia affecting millions of people around the world. Therapeutic development has focused on the problem of the loss of basal forebrain cholinergic function, as it is the only evidence responsible for brain neurodegeneration in patients with Alzheimer’s disease. Several attempts to improve cholinergic neurotransmission have been investigated by minimizing synaptic degradation of acetylcholine using acetylcholinesterase inhibitors. In the current study, we explore the designing of a new series of nicotinonitrile-coumarin hybrids as potential acetylcholinesterase inhibitors. The new hybrids were prepared utilizing pyridine-2(1H)-thiones as starting precursors. The in vitro acetylcholinesterase (AChE) inhibitory activities were examined for the new nicotinonitrile-coumarin hybrid molecules, when compared with donepezil as a standard drug with IC50 of 14 nM. Coumarin derivative, linked to 6-(4-nitrophenyl)-4-phenylnicotinonitrile, showed more effective inhibitory activity than the reference donepezil with IC50 of 13 nM. The free radical-scavenging capabilities against DPPH of the new hybrid derivatives were screened. Additionally, their in vitro cytotoxic activities have been tested against various eukaryotic cells. Furthermore, docking study showed excellent interaction between nicotinonitrile-coumarin hybrids and AChE.
Graphic abstract
Similar content being viewed by others
References
https://www.who.int/news-room/fact-sheets/detail/dementia. Accessed 19 Sept 2019
Y. Huang, L. Mucke, Cell 148(6), 1204 (2012)
A. Kumar, A. Singh, Pharmacol. Rep. 67(2), 195 (2015)
H. Sugimoto, Y. Yamanishi, Y. Iimura, Y. Kawakami, Curr. Med. Chem. 7, 303 (2000)
J. Trujillo-Ferrara, L. Montoya Cano, M. Espinoza-Fonseca, Bioorg. Med. Chem. Lett. 13, 1825 (2003)
A.V. Terry Jr., J.J. Buccafusco, J. Pharmacol. Exp. Ther. 306, 821 (2003)
D.J. Selkoe, Physiol. Rev. 81, 741 (2001)
M. Weinstock, E. Groner, Chem. Biol. Interact. 175, 216 (2008)
D.R. Liston, J.A. Nielsen, A. Villalobos, D. Chapin, S.B. Jones, S.T. Hubbard, I.A. Shalaby, A. Ramirez, D. Nason, W.F. White, Eur. J. Pharmacol. 486, 9 (2004)
C. Mustazza, A. Borioni, M.R. Del Giudice, F. Gatta, R. Ferretti, A. Meneguz, M.T. Volpe, P. Lorenzini, Eur. J. Med. Chem. 37, 91 (2002)
S.F. Razavi, M. Khoobi, H. Nadri, A. Sakhteman, A. Moradi, S. Emami, Eur. J. Med. Chem. 46, 252 (2013)
M.T.H. Khan, New Biotechnol. 5, 331 (2009)
J. Zhang, D. Zhu, R. Sheng, H. Wu, Y. Hu, F. Wang, T. Cai, B. Yang, Q. He, Eur. J. Pharmacol. 613, 1 (2009)
S.V. Nukoolkarn, S. Saen-oon, T. Rungrotmongkol, S. Hannongbua, K. Ingkaninan, K. Suwanborirux, Bioorg. Med. Chem. 16, 6560 (2008)
P.K. Mukherjee, V. Kumar, M. Mal, P.J. Houghton, Phytomedicine 14, 289 (2007)
A.E.M. Mekky, S.M.H. Sanad, Synth. Commun. 49, 1385 (2019). https://doi.org/10.1080/00397911.2019.1595658
R. Bullock, A. Dengiz, Int. J. Clin. Pract. 59, 817 (2005)
M. Racchi, M. Mazzucchelli, E. Porrello, C. Lanni, S. Govoni, Pharmacol. Res. 50, 441 (2004)
J. Rodda, J. Carter, BMJ 344, e2986 (2012)
D. Patel, P. Kumari, N.B. Patel, Med. Chem. Res. 22, 726 (2013)
J.M. Timonen, R.M. Nieminen, O. Sareila, A. Goulas, L.J. Moilanen, M. Haukka, P. Vainiotalo, E. Moilanen, P.H. Aulaskari, Eur. J. Med. Chem. 46, 3845 (2011)
M.E. Riveiro, N. De Kimpe, A. Moglioni, R. Vazquez, F. Monczor, C. Shayo, C. Davio, Curr. Med. Chem. 17, 1325 (2010)
P. Anand, B. Singh, N.A. Singh, Bioorg. Med. Chem. 20, 1175 (2012)
K.Y. Wong, P.R. Duchowicz, A.G. Mercader, E.A. Castro, Mini-Rev. Med. Chem. 12, 936 (2012)
M.J. Matos, D. Viña, P. Janeiro, F. Borges, L. Santana, E. Uriarte, Bioorg. Med. Chem. Lett. 20, 5157 (2010)
A. Gomez-Outes, M. Luisa Suarez-Gea, G. Calvo-Rojas, R. Lecumberri, E. Rocha, C. Pozo-Hernández, I.A. Terleira-Fernandez, E. Vargas-Castrillón, Curr. Drug Discov. Technol. 9, 83 (2012)
S. Hamulakova, L. Janovec, M. Hrabinova, K. Spilovska, J. Korabecny, P. Kristian, K. Kuca, J. Imrich, J. Med. Chem. 57, 7073 (2014)
M. Alipour, M. Khoobi, A. Foroumadi, H. Nadri, A. Moradi, A. Sakhteman, M. Ghandi, A. Shafiee, Bioorg. Med. Chem. 20(24), 7214 (2012)
A. Asadipour, M. Alipour, M. Jafari, M. Khoobi, S. Emami, H. Nadri, A. Sakhteman, A. Moradi, V. Sheibani, F.H. Moghadam, A. Shafiee, Eur. J. Med. Chem. 70, 623 (2013)
M. Catto, L. Pisani, F. Leonetti, O. Nicolotti, P. Pesce, A. Stefanachi, S. Cellamare, A. Carotti, Bioorg. Med. Chem. 20, 146 (2013)
A.E.M. Mekky, S.M.H. Sanad, Bioorg. Chem. 102, 104094 (2020). https://doi.org/10.1016/j.bioorg.2020.104094
S.M.H. Sanad, A.E.M. Mekky, J. Iran. Chem. Soc. (2020). https://doi.org/10.1007/s13738-020-01987-y
S.M.H. Sanad, A.E.M. Mekky, ChemistrySelect. 5(28), 8494 (2020). https://doi.org/10.1002/slct.202001208
K.A. Alamry, T.S. Saleh, A.E.M. Mekky, M.A. Hussein, Polymer 189, 122123 (2020). https://doi.org/10.1016/j.polymer.2019.122123
S.M.H. Sanad, A.E.M. Mekky, J. Heterocycl. Chem. (2020). https://doi.org/10.1002/jhet.4021
A.E.M. Mekky, S.M.H. Sanad, A.Y. Said, M.A.A. Elneairy, Synth. Commun. 50(15), 2376 (2020). https://doi.org/10.1080/00397911.2020.1778033
S.M.H. Sanad, A.E.M. Mekky, Synth. Commun. 50(10), 1468 (2020). https://doi.org/10.1080/00397911.2020.1743318
A. Fuentes, J.M. Marinasand, J.V. Sinisterra, Tetrahedron Lett. 28(39), 4541 (1987)
J.R. Schmink, J.L. Holcomb, N.E. Leadbeater, Org. Lett. 11(2), 365 (2008)
L. Rasheed, A. Hasan, Asian J. Chem. 19(7), 5057 (2007)
W.T.A. Harrison, H.S. Yathirajan, B.K. Sarojini, B. Narayana, J. Indira, Acta Cryst. E62, o1647 (2006)
M.Y. Wani, A.R. Bhat, A. Azam, D.H. Lee, I. Choi, F. Athar, Eur. J. Med. Chem. 54, 845 (2012)
S.M.H. Sanad, M.I.M. Hefny, A.A.M. Ahmed, M.A.A. Elneairy, J. Heterocycl. Chem. 55(9), 2046 (2018). https://doi.org/10.1002/jhet.3239
G.H. Elgemeie, Heterocycles 31(1), 123 (1990)
M.A.E. Hawass, S.M.H. Sanad, A.A.M. Ahmed, M.A.A. Elneairy, J. Sulfur Chem. 39(4), 388 (2018). https://doi.org/10.1080/17415993.2018.1435657
S. Guieu, J. Rocha, A.M. Silva, Synlett 24, 762 (2013)
G.L. Ellman, K.D. Courtney, V. Andres Jr., R.M. Featherstone, Biochem. Pharm. 7(2), 88 (1961)
M. Alipour, M. Khoobi, A. Foroumadi, H. Nadri, A. Moradi, A. Sakhteman, M. Ghandi, A. Shafiee, Bioorg. Med. Chem. 20(24), 7214 (2020)
C. Hansch, A. Leo, A.R.W. Taft, Chem. Rev. 91, 165 (1991)
T.H. Ferreira-Vieira, I.M. Guimaraes, F.R. Silva, F.M. Ribeiro, Curr. Neuropharmacol. 14, 101 (2016)
G.L. Warren, C.W. Andrews, A.M. Capelli, B. Clarke, J. LaLonde, M.H. Lambert, M. Lindvall, N. Nevins, S.F. Semus, S. Senger, G. Tedesco, J. Med. Chem. 49, 5912 (2006)
C. Scholz, S. Knorr, K. Hamacher, B. Schmidt, J. Chem. Inf. Model. 55, 398 (2015)
S. Vilar, G. Cozza, S. Moro, Curr. Top. Med. Chem. 8, 1555 (2008)
T.T. Lan, D.T. Anh, E.J. Park, H.W. Jeon, J.S. Kang, N.T. Thuan, S.B. Han, N.H. Nam, Med. Chem. Res. 29(3), 396 (2020)
P.T. Thuong, M.K. Na, N.H. Dang, T.M. Hung, P.T. Ky, T.V. Thanh, N.H. Nam, N.D. Thuan, D.E. Sok, K.H. Bae, Nat. Prod. Sci. 12(1), 29 (2006)
S.M.H. Sanad, D.H. Hanna, A.E.M. Mekky, J. Mol. Struct. 1188, 214 (2019)
G. Repetto, A. Del Peso, J.L. Zurita, Nat. Protoc. 3(7), 1125 (2008)
Molecular Operating Environment (MOE) 2019.01 (Chemical Computing Group ULC, Montreal, QC, Canada 2020)
G. Neudert, G. Klebe, J. Chem. Inf. Model. 51, 2731 (2011)
C. Roca, C. Requena, V. Sebastian-Perez, S. Malhotra, C. Radoux, C. Perez, A. Martinez, J. Antonio Paez, T.L. Blundell, N.E. Campillo, J. Enzyme Inhib. Med. Chem. 33(1), 1034 (2018)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sanad, S.M.H., Mekky, A.E.M. Novel nicotinonitrile-coumarin hybrids as potential acetylcholinesterase inhibitors: design, synthesis, in vitro and in silico studies. J IRAN CHEM SOC 18, 213–224 (2021). https://doi.org/10.1007/s13738-020-02018-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13738-020-02018-6