Abstract
Background: Considering that AD is multifactorial in nature, novel series of imidazo [2,1-b][1,3,4] thiadiazole derivatives were designed to address the basic factors responsible for the disease.
Methods: These compounds were investigated as inhibitors of beta-site APP cleaving enzyme 1, acetylcholinesterase and butyryl cholinesterase.
Results: The BACE1 inhibitory results indicated that nitro phenyl substituted derivatives of imidazo [2,1-b][1,3,4] thiadiazole scaffold (R2 = m-NO2) demonstrated superior BACE1 inhibitory activity compared to other substituted moieties. In the BuChE assay, compounds 4h and 4l carrying meta NO2 at R2 of phenyl ring turned out to be potent inhibitors.
Conclusion: In conclusion, these novel synthesized derivatives seem to be promising anti-Alzheimer agents.
Keywords: Alzheimer's disease, BACE1, Imidazo[2, 1-b][1, 3, 4] thiadiazol, AChE, BuChE, synthesize.
Graphical Abstract
[1]
Gulhan, T-Z. Fighting against Alzheimer’s Disease: Synthesis of new pyrazoline and benzothiazole derivatives as new acetylcholinesterase and MAO inhibitors. Lett. Drug Des. Discov., 2018, 15(4), 414-427.
[http://dx.doi.org/10.2174/1570180814666170704144917]
[http://dx.doi.org/10.2174/1570180814666170704144917]
[2]
Crews, L.; Masliah, E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum. Mol. Genet., 2010, 19(R1), R12-R20.
[http://dx.doi.org/10.1093/hmg/ddq160] [PMID: 20413653]
[http://dx.doi.org/10.1093/hmg/ddq160] [PMID: 20413653]
[3]
Lu, R-C. Heat shock protein 70 in Alzheimer’s disease. BioMed Res. Int., 2014.
[http://dx.doi.org/10.1155/2014/435203]
[http://dx.doi.org/10.1155/2014/435203]
[4]
Maryam, N. Design, Synthesis and Characterization of Novel Urolithin Derivatives as Cholinesterase Inhibitor Agents. Lett. Drug Des. Discov., 2018, 15(11), 1131-1140.
[http://dx.doi.org/10.2174/1570180815666180115144608]
[http://dx.doi.org/10.2174/1570180815666180115144608]
[5]
Chen, S-C.; Qiu, G.L.; Li, B.; Shi, J.B.; Liu, X.H.; Tang, W.J. Tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one scaffold derivatives: Synthesis and biological evaluation as selective BuChE inhibitors. Eur. J. Med. Chem., 2018, 147, 194-204.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.002] [PMID: 29438888]
[http://dx.doi.org/10.1016/j.ejmech.2018.02.002] [PMID: 29438888]
[6]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[7]
Weisman, D.; Hakimian, E.; Ho, G.J. Interleukins, inflammation, and mechanisms of Alzheimer’s disease. Vitam. Horm., 2006, 74, 505-530.
[http://dx.doi.org/10.1016/S0083-6729(06)74020-1] [PMID: 17027528]
[http://dx.doi.org/10.1016/S0083-6729(06)74020-1] [PMID: 17027528]
[8]
Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem., 2011, 18(32), 4949-4975.
[http://dx.doi.org/10.2174/092986711797535245] [PMID: 22050745]
[http://dx.doi.org/10.2174/092986711797535245] [PMID: 22050745]
[9]
Sonkusare, S.K.; Kaul, C.L.; Ramarao, P. Dementia of Alzheimer’s disease and other neurodegenerative disorders--memantine, a new hope. Pharmacol. Res., 2005, 51(1), 1-17.
[http://dx.doi.org/10.1016/j.phrs.2004.05.005] [PMID: 15519530]
[http://dx.doi.org/10.1016/j.phrs.2004.05.005] [PMID: 15519530]
[10]
Raina, P.; Santaguida, P.; Ismaila, A.; Patterson, C.; Cowan, D.; Levine, M.; Booker, L.; Oremus, M. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann. Intern. Med., 2008, 148(5), 379-397.
[http://dx.doi.org/10.7326/0003-4819-148-5-200803040-00009] [PMID: 18316756]
[http://dx.doi.org/10.7326/0003-4819-148-5-200803040-00009] [PMID: 18316756]
[11]
De Strooper, B.; Vassar, R.; Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol., 2010, 6(2), 99-107.
[http://dx.doi.org/10.1038/nrneurol.2009.218] [PMID: 20139999]
[http://dx.doi.org/10.1038/nrneurol.2009.218] [PMID: 20139999]
[12]
Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(9), 89.
[http://dx.doi.org/10.1186/s13195-014-0089-7] [PMID: 25621019]
[http://dx.doi.org/10.1186/s13195-014-0089-7] [PMID: 25621019]
[13]
Fobare, W.F.; Solvibile, W.R.; Robichaud, A.J.; Malamas, M.S.; Manas, E.; Turner, J.; Hu, Y.; Wagner, E.; Chopra, R.; Cowling, R.; Jin, G.; Bard, J. Thiophene substituted acylguanidines as BACE1 inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(19), 5353-5356.
[http://dx.doi.org/10.1016/j.bmcl.2007.08.010] [PMID: 17761418]
[http://dx.doi.org/10.1016/j.bmcl.2007.08.010] [PMID: 17761418]
[14]
Iraji, A.; Firuzi, O.; Khoshneviszadeh, M.; Tavakkoli, M.; Mahdavi, M.; Nadri, H.; Edraki, N.; Miri, R. Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer’s disease. Eur. J. Med. Chem., 2017, 141, 690-702.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.057] [PMID: 29107423]
[http://dx.doi.org/10.1016/j.ejmech.2017.09.057] [PMID: 29107423]
[15]
Edraki, N.; Firuzi, O.; Foroumadi, A.; Miri, R.; Madadkar-Sobhani, A.; Khoshneviszadeh, M.; Shafiee, A. Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-secretase (BACE1). Bioorg. Med. Chem., 2013, 21(8), 2396-2412.
[http://dx.doi.org/10.1016/j.bmc.2013.01.064] [PMID: 23480856]
[http://dx.doi.org/10.1016/j.bmc.2013.01.064] [PMID: 23480856]
[16]
Gerritz, S.W.; Zhai, W.; Shi, S.; Zhu, S.; Toyn, J.H.; Meredith, J.E., Jr; Iben, L.G.; Burton, C.R.; Albright, C.F.; Good, A.C.; Tebben, A.J.; Muckelbauer, J.K.; Camac, D.M.; Metzler, W.; Cook, L.S.; Padmanabha, R.; Lentz, K.A.; Sofia, M.J.; Poss, M.A.; Macor, J.E.; Thompson, L.A., III Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J. Med. Chem., 2012, 55(21), 9208-9223.
[http://dx.doi.org/10.1021/jm300931y] [PMID: 23030502]
[http://dx.doi.org/10.1021/jm300931y] [PMID: 23030502]
[17]
Iraji, A.; Firuzi, O.; Khoshneviszadeh, M.; Nadri, H.; Edraki, N.; Miri, R. Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer’s disease. Bioorg. Chem., 2018, 77, 223-235.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.017] [PMID: 29367079]
[http://dx.doi.org/10.1016/j.bioorg.2018.01.017] [PMID: 29367079]
[18]
Malamas, M.S.; Erdei, J.; Gunawan, I.; Barnes, K.; Johnson, M.; Hui, Y.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.; Olland, A.; Bard, J.; Robichaud, A.J. Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors. J. Med. Chem., 2009, 52(20), 6314-6323.
[http://dx.doi.org/10.1021/jm9006752] [PMID: 19757823]
[http://dx.doi.org/10.1021/jm9006752] [PMID: 19757823]
[19]
Malamas, M.S.; Erdei, J.; Gunawan, I.; Barnes, K.; Hui, Y.; Johnson, M.; Robichaud, A.; Zhou, P.; Yan, Y.; Solvibile, W.; Turner, J.; Fan, K.Y.; Chopra, R.; Bard, J.; Pangalos, M.N. New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: exploring the S2′ region. Bioorg. Med. Chem. Lett., 2011, 21(18), 5164-5170.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.057] [PMID: 21835615]
[http://dx.doi.org/10.1016/j.bmcl.2011.07.057] [PMID: 21835615]
[20]
Ghosh, A.K.; Brindisi, M.; Tang, J. Developing β-secretase inhibitors for treatment of Alzheimer’s disease. J. Neurochem., 2012, 120(Suppl. 1), 71-83.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07476.x] [PMID: 22122681]
[http://dx.doi.org/10.1111/j.1471-4159.2011.07476.x] [PMID: 22122681]
[21]
Qu, W.; Kung, M.P.; Hou, C.; Oya, S.; Kung, H.F. Quick assembly of 1,4-diphenyltriazoles as probes targeting β-amyloid aggregates in Alzheimer’s disease. J. Med. Chem., 2007, 50(14), 3380-3387.
[http://dx.doi.org/10.1021/jm070467l] [PMID: 17569520]
[http://dx.doi.org/10.1021/jm070467l] [PMID: 17569520]
[22]
Delgado, O.; Delgado, F.; Vega, J.A.; Trabanco, A.A. N-Bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders. Eur. J. Med. Chem., 2015, 97, 719-731.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.034] [PMID: 25542766]
[http://dx.doi.org/10.1016/j.ejmech.2014.12.034] [PMID: 25542766]
[23]
Kethiri, R.R.; Bakthavatchalam, R. Leucine-rich repeat kinase 2 inhibitors: A review of recent patents (2011 - 2013). Expert Opin. Ther. Pat., 2014, 24(7), 745-757.
[http://dx.doi.org/10.1517/13543776.2014.907275] [PMID: 24918198]
[http://dx.doi.org/10.1517/13543776.2014.907275] [PMID: 24918198]
[24]
Al-Tel, T.H.; Semreen, M.H.; Al-Qawasmeh, R.A.; Schmidt, M.F.; El-Awadi, R.; Ardah, M.; Zaarour, R.; Rao, S.N.; El-Agnaf, O. Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer’s drug leads. J. Med. Chem., 2011, 54(24), 8373-8385.
[http://dx.doi.org/10.1021/jm201181f] [PMID: 22044119]
[http://dx.doi.org/10.1021/jm201181f] [PMID: 22044119]
[25]
Maillard, M.C.; Hom, R.K.; Benson, T.E.; Moon, J.B.; Mamo, S.; Bienkowski, M.; Tomasselli, A.G.; Woods, D.D.; Prince, D.B.; Paddock, D.J.; Emmons, T.L.; Tucker, J.A.; Dappen, M.S.; Brogley, L.; Thorsett, E.D.; Jewett, N.; Sinha, S.; John, V. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase. J. Med. Chem., 2007, 50(4), 776-781.
[http://dx.doi.org/10.1021/jm061242y] [PMID: 17300163]
[http://dx.doi.org/10.1021/jm061242y] [PMID: 17300163]
[26]
Gurjar, A.S.; Andrisano, V.; Simone, A.D.; Velingkar, V.S. Design, synthesis, in silico and in vitro screening of 1,2,4-thiadiazole analogues as non-peptide inhibitors of beta-secretase. Bioorg. Chem., 2014, 57, 90-98.
[http://dx.doi.org/10.1016/j.bioorg.2014.09.002] [PMID: 25303313]
[http://dx.doi.org/10.1016/j.bioorg.2014.09.002] [PMID: 25303313]
[27]
Azimi, S.; Zonouzi, A.; Firuzi, O.; Iraji, A.; Saeedi, M.; Mahdavi, M.; Edraki, N. Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis. Eur. J. Med. Chem., 2017, 138, 729-737.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.040] [PMID: 28728105]
[http://dx.doi.org/10.1016/j.ejmech.2017.06.040] [PMID: 28728105]
[28]
Edraki, N.; Firuzi, O.; Fatahi, Y.; Mahdavi, M.; Asadi, M.; Emami, S.; Divsalar, K.; Miri, R.; Iraji, A.; Khoshneviszadeh, M.; Firoozpour, L.; Shafiee, A.; Foroumadi, A. N-(2-(Piperazin-1-yl)phenyl)arylamide derivatives as β-Secretase (BACE1) inhibitors: Simple synthesis by UGI four-component reaction and biological evaluation. Arch. Pharm. (Weinheim), 2015, 348(5), 330-337.
[http://dx.doi.org/10.1002/ardp.201400322] [PMID: 25787800]
[http://dx.doi.org/10.1002/ardp.201400322] [PMID: 25787800]
[29]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, 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]
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[30]
Kumar, D.; Gupta, S.K.; Ganeshpurkar, A.; Gutti, G.; Krishnamurthy, S.; Modi, G.; Singh, S.K. Development of piperazinediones as dual inhibitor for treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2018, 150, 87-101.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.078] [PMID: 29524731]
[http://dx.doi.org/10.1016/j.ejmech.2018.02.078] [PMID: 29524731]
[31]
Badran, M.M.; Abdel Hakeem, M.; Abuel-Maaty, S.M.; El-Malah, A.; Abdel Salam, R.M. Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer’s disease. Arch. Pharm. (Weinheim), 2010, 343(10), 590-601.
[http://dx.doi.org/10.1002/ardp.200900226] [PMID: 20925094]
[http://dx.doi.org/10.1002/ardp.200900226] [PMID: 20925094]
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