Drug Design of Inhibitors of Alzheimer’s Disease (AD): POM and DFT Analyses of Cholinesterase Inhibitory Activity of β-amino di-Carbonyl Derivatives

Author(s): Taibi Ben Hadda*, Abdur Rauf, Hsaine Zgou, Fatma Sezer Senol, Ilkay Erdogan Orhan, Yahia Nasser Mabkhot*, Ismail I. Althagafi, Thoraya A. Farghaly*, Seham Alterary.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 8 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Since deficit of acetylcholine has been evidenced in the Alzheimer’s disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD.

Method: In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 μg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity.

Results and Conclusion: All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.

Keywords: β-Amino dicarbonyl, cholinesterase inhibition, Alzheimer’s disease (AD), DFT calculations, Petra/Osiris/ Molinspiration (POM) analysis, in vitro.

Schneider, L.S.; Mangialasche, F.; Andreasen, N.; Feldman, H.; Giacobini, E.; Jones, R.; Mantua, V.; Mecocci, P.; Pani, L.; Winblad, B.; Kivipelto, M. Clinical trials and late-stage drug development for Alzheimer’s disease: An appraisal from 1984 to 2014. J. Intern. Med., 2014, 275, 251-283.
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36i, 375-399.
Orhan, I.E.; Senol, F.S.; Ozturk, N.; Celik, S.A.; Pulur, A.; Kan, Y. Phytochemical contents and enzyme inhibitory and antioxidant properties of Anethum graveolens L. (dill) samples cultivated under organic and conventional agricultural conditions. Food Chem. Toxicol., 2013, 59, 96-103.
Senol, F.S.; Orhan, I.E.; Ozgen, U.; Renda, G.; Bulut, G.; Guven, L.; Karaoglan, E.S.; Sevindik, H.G.; Skalicka-Wozniak, K.; Caliskan, U.K.; Sekeroglu, N. Memory-vitalizing effect of twenty-five medicinal and edible plants and their isolated compounds. S. Afr. J. Bot., 2016, 102, 102-109.
Orhan, I.E.; Orhan, G.; Gurkas, E. An overview on natural cholinesterase inhibitors - A multi-targeted drug class - and their mass production. Mini Rev. Med. Chem., 2011, 11, 836-842.
Jellinger, K.A. The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations. Int. Rev. Neurobiol., 2013, 110, 1-47.
Meskini, I.; Toupet, L.; Daoudi, M.; Kerbal, A.; Bennani, B.; Dixneuf, P.H.; Chohan, Z.H.; Leite, A.C.L.; Ben Hadda, T. An efficient protocol for accessing β-amino dicarbonyl compounds through aza-Michael reaction. J. Braz. Chem. Soc., 2010, 21(6), 1129-1135.
Meskini, I.; Daoudi, M.; Daran, J-C.; Zouihri, H.; Ben Hadda, T. Diethyl 2-[(N-benzyl-N-methylamino)-(phenyl)methyl]propanedioate. Acta Crystallogr., 2010, E66, o746.
Ellman, G.L.; Courtney, K.D.; Andres, V.; Featherstone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
Georgiev, M.; Alipieva, K.; Orhan, I.; Abrashev, R.; Denev, P.; Angelova, M. Antioxidant and cholinesterases inhibitory activities of Verbascum xanthophoeniceum Griseb. and its phenylethanoid glycosides. Food Chem., 2011, 128, 100-105.
Chua, M.T.; Tung, Y.T.; Chang, S.T. Antioxidant activities of ethanolic extracts from the twigs of Cinnamomum osmophleum. Bioresour. Technol., 2008, 99, 1918-1925.
Yilmaz, B.S.; Altun, M.L.; Orhan, I.E.; Ergene, B.; Citoglu, G.S. Enzyme inhibitory and antioxidant activities of Viburnum tinus L. relevant to its neuroprotective potential. Food Chem., 2013, 141, 582-588.
Becke, A.D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 1993, 98, 5648-5652.
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B, 1988, 3, 785-789.
Ben Hadda, T.; Srivastava, S.; Das, B.; Salgado-Zamora, H.; Shaheen, U.; Bader, A.; Naseer, M.M. POM analyses of antimicrobial activity of some 2, 3-armed 4, 5, 6, 7-tetrahydro-1-benzothiophenes: favourable and unfavourable physico-chemical parameters in design of antibacterial and mycolytic agents. Med. Chem. Res., 2014, 23, 995-1003.
Ben Hadda, T.; Ali, M.A.; Masand, V.; Gharby, S.; Fergoug, T.; Warad, I. Tautomeric origin of dual effects of N1-nicotinoyl-3-(4′-hydroxy-3′-methyl phenyl)-5-[(sub) phenyl]-2-pyrazolines on bacterial and viral strains: POM analyses as new efficient bioinformatics’ platform to predict and optimize bioactivity of drugs. Med. Chem. Res., 2013, 22, 1438-1449.
Ben Hadda, T.; Fergoug, T.; Warad, I. POM Theoretical calculations and experimental verification of antibacterial potential of 5-hydroxy-4-(substituted-amino)-2(5H)-furanones. Res. Chem. Intermed., 2013, 39, 1963-1974.
Ben Hadda, T.; Genc, Z.K.; Masand, V.H.; Nebbache, N.; Warad, I.; Jodeh, S.; Genc, M.; Mabkhot, Y.N.; Barakat, A.; Salgado-Zamora, H. Computational POM and DFT evaluation of experimental in vitro cancer inhibition of staurosporine-ruthenium(II) complexes: the power force of organometallics in drug design. Acta Chim. Slov., 2015, 62, 679.
Bennani, B.; Kerbal, A.; Daoudi, M.; Baba, B.F.; Al-Houari, G.; Jalbout, A.F.; Mimouni, M.; Benazza, M.; Demailly, G.; Akkurt, M.; Yildirim, S.Ö.; Ben Hadda, T. Combined drug design of potential Mycobacterium tuberculosis and HIV-1 inhibitors: 3′, 4′-di-substituted-4′ H-spiro [isothiochromene-3, 5′-isoxazol]-4 (1H)-one. ARKIVOC, 2007, 16, 19-40.
Chohan, Z.H.; Sumrra, S.H.; Youssoufi, M.H.; Ben Hadda, T. Design and Synthesis of Triazole Schiff bases and their Oxovanadium (IV) complexes as antimicrobial agents. Eur. J. Med. Chem., 2010, 45, 2739-2749. a
Chohan, Z.H.; Youssoufi, M.H.; Jarrahpour, A.; Ben Hadda, T. Identification of antibacterial and antifungal pharmacophore sites for potent bacteria and fungi inhibition: indolenyl sulfonamide derivatives. Eur. J. Med. Chem., 2010, 45, 1189-1199.
Chohan, Z.H.; Sumrra, S.H.; Youssoufi, M.H.; Ben Hadda, T. Design and synthesis of triazole Schiff bases and their oxovanadium (IV) complexes as antimicrobial agents. J. Coord. Chem., 2010, 63, 3981-3998.
Fathi, J.; Masand, V.; Jawarkar, R.; Mouhoub, R.; Ben Hadda, T. POM as efficient tools to predict and improve both antibacterial and antifungal activity of aryl aldazines. J. Comput. Method. Mol. Design, 2011, 1, 57-68.
Jarrahpour, A.; Fathi, J.; Mimouni, M.; Ben Hadda, T.; Sheikh, J.; Chohan, Z.H.; Parvez, A. Petra, Osiris and Molinspiration (POM) together as a successful support in drug design: antibacterial activity and biopharmaceutical characterization of some azo Schiff bases. Med. Chem. Res., 2012, 21, 1984-1990.
Jarrahpour, A.; Motamedifar, M.; Zarei, M.; Youssoufi, M.H.; Mimouni, M.; Chohan, Z.H.; Ben Hadda, T. Petra, Osiris, and Molinspiration together as a guide in drug design: predictions and correlation structure/antibacterial activity relationships of new N-sulfonyl monocyclic β-lactams. Phosphorus Sulfur Silicon Relat. Elem., 2010, 185, 491-497.
Mabkhot, Y.N.; Al-Majid, A.M.; Barakat, A.; Al-Showiman, S.S.; Al-Har, M.S.; Radi, S.; Naseer, M.M.; Ben Hadda, T. Synthesis and biological evaluation of 2-aminobenzamide derivatives as antimicrobial agents: opening/closing pharmacophore site. Int. J. Mol. Sci., 2014, 15, 5115-5127.
Parvez, A.; Jyotsna, M.; Youssoufi, M.H.; Ben Hadda, T. Antibacterial potential of some monocyclic β-lactams containing two synergetic buried antibacterial pharmacophore sites. Phosphorus Sulfur Silicon Relat. Elem., 2010, 185, 1500-1510.
Sheikh, J.; Hatzade, K.; Bader, A.; Shaheen, U.; Sander, T.; Ben Hadda, T. Computational evaluation and experimental verification of antibacterial and antioxidant activity of 7-hydroxy-3-pyrazolyl-4H-chromen-4-ones and their o-glucosides: identification of pharmacophore sites. Med. Chem. Res., 2014, 23, 243-251.
Sheikh, J.; Parvez, A.; Ingle, V.; Juneja, H.; Dongre, R.; Chohan, Z.H.; Youssoufi, M.H.; Ben Hadda, T. Synthesis, biopharmaceutical characterization, antimicrobial and antioxidant activities of 1-(4′-O-β-d-glucopyranosyloxy- 2′-hydroxyphenyl)-3-aryl-propane-1, 3-diones. Eur. J. Med. Chem., 2011, 46, 1390-1399.
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46, 3-26.
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1, 337-341.
Mabkhot, Yahia N., Muhammad Arfan, Hsaine Zgou, Zuhal K. Genc, Murat Genc, Abdur Rauf, Saud Bawazeer, and Taibi Ben Hadda, How to improve antifungal bioactivity: POM and DFT study of some chiral amides derivatives of diacetyl-L-tartaric acid and amines. Res. Chem. Intermed., 2016, 42, 8055-8068.
Uddin, N.; Sirajuddin, M.; Uddin, N.; Tariq, M.; Ullah, H.; Ali, S.; Tirmizi, S.A.; Khan, A.R. Synthesis, spectroscopic characterization, biological screenings, DNA binding study and POM analyses of transition metal carboxylates. Spectrochim. Acta Part A Mol. Biomol. Spectrosc., 2015, 140, 563-574.
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A. Gaussian98 Rev. A.11.3; Gaussian: Pittsburgh, PA, USA, 2002.
Jogi, P.S.; Meshram, J.; Sheikh, J.; Hadda, T.B. Synthesis, biopharmaceutical characterization, and antimicrobial study of novel azo dyes of 7-hydroxy-4-methylcoumarin. Med. Chem. Res., 2013, 22, 4202-4210.
Mabkhot, Y.N.; Alatibi, F.; El-Sayed, N.N.E.; Al-Showiman, S.; Kheder, N.A.; Wadood, A.; Rauf, A.; Bawazeer, S.; Hadda, T.B. Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses. Molecules, 2016, 21(2), 222.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [688 - 705]
Pages: 18
DOI: 10.2174/1389557518666181102102816
Price: $58

Article Metrics

PDF: 12