Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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

Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases

Author(s): Viktoriya Ivasiv, Claudia Albertini, Ana E. Gonçalves, Michele Rossi and Maria L. Bolognesi*

Volume 19, Issue 19, 2019

Page: [1694 - 1711] Pages: 18

DOI: 10.2174/1568026619666190619115735

Price: $65

Abstract

Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in a new, single chemical entity. Recently, it has been recognized as an effective approach to design ligands able to modulate multiple targets of interest. Hybrid compounds can be obtained by linking (presence of a linker) or framework integration (merging or fusing) strategies. Although very promising to combat the multifactorial nature of complex diseases, the development of molecular hybrids faces the critical issues of selecting the right target combination and the achievement of a balanced activity towards them, while maintaining drug-like-properties. In this review, we present recent case histories from our own research group that demonstrate why and how molecular hybridization can be carried out to address the challenges of multitarget drug discovery in two therapeutic areas that are Alzheimer’s and parasitic diseases. Selected examples spanning from linker- to fragment- based hybrids will allow to discuss issues and consequences relevant to drug design.

Keywords: Hybrids, Framework combination, Alzheimer's disease, Parasitic disease, Multitarget drug discovery, Fragmentbased drug discovery.

« Previous Next »
Graphical Abstract

[1]
Decker, M. Design of hybrid molecules for drug development, (1st ed); Elsevier, 2017, p. 352.
[2]
Ariëns, E.J. Stereochemical implications of hybrid and pseudo-hybrid drugs. Part III. Med. Res. Rev., 1988, 8(2), 309-320.
[http://dx.doi.org/10.1002/med.2610080206] [PMID: 3288823]
[3]
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14(17), 1829-1852.
[http://dx.doi.org/10.2174/092986707781058805] [PMID: 17627520]
[4]
Jones, L.H.; Allan, G.; Barba, O.; Burt, C.; Corbau, R.; Dupont, T.; Knöchel, T.; Irving, S.; Middleton, D.S.; Mowbray, C.E.; Perros, M.; Ringrose, H.; Swain, N.A.; Webster, R.; Westby, M.; Phillips, C. Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays. J. Med. Chem., 2009, 52(4), 1219-1223.
[http://dx.doi.org/10.1021/jm801322h] [PMID: 19175319]
[5]
Harrison, J.R.; Brand, S.; Smith, V.; Robinson, D.A.; Thompson, S.; Smith, A.; Davies, K.; Mok, N.; Torrie, L.S.; Collie, I.; Hallyburton, I.; Norval, S.; Simeons, F.R.C.; Stojanovski, L.; Frearson, J.A.; Brenk, R.; Wyatt, P.G.; Gilbert, I.H.; Read, K.D. A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant N-myristoyltransferase inhibitors. J. Med. Chem., 2018, 61(18), 8374-8389.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00884] [PMID: 30207721]
[6]
Scotti, L.; Mendonca-Junior, F.J.; Scotti, M.T. Editorial: Hybrid compounds as multitarget agents in medicinal chemistry - Part I. Curr. Top. Med. Chem., 2017, 17(8), 843-844.
[http://dx.doi.org/10.2174/156802661708170126200430] [PMID: 28406078]
[7]
Scotti, L.; Mendonça-Junior, F.J.; Scotti, M.T. Editorial (Thematic Issue: Hybrid compounds as multitarget agents in medicinal Chemistry - Part II). Curr. Top. Med. Chem., 2017, 17(9), 957-958.
[http://dx.doi.org/10.2174/156802661709170213205211] [PMID: 28406075]
[8]
Prati, F.; Uliassi, E.; Bolognesi, M. Two diseases, one approach: Multitarget drug discovery in Alzheimer’s and neglected tropical diseases. MedChemComm, 2014, 5(7), 853-861.
[http://dx.doi.org/10.1039/C4MD00069B]
[9]
Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery and polypharmacology. ChemMedChem, 2016, 11(12), 1190-1192.
[http://dx.doi.org/10.1002/cmdc.201600161] [PMID: 27061625]
[10]
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[11]
Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51(3), 347-372.
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[12]
Bolognesi, M.L. Polypharmacology in a single drug: Multitarget drugs. Curr. Med. Chem., 2013, 20(13), 1639-1645.
[http://dx.doi.org/10.2174/0929867311320130004] [PMID: 23410164]
[13]
Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today, 2004, 9(15), 641-651.
[http://dx.doi.org/10.1016/S1359-6446(04)03163-0] [PMID: 15279847]
[14]
Morphy, R.; Rankovic, Z. Designing multiple ligands- medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15(6), 587-600.
[http://dx.doi.org/10.2174/138161209787315594] [PMID: 19199984]
[15]
Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med., 2018, 7(1), 3.
[http://dx.doi.org/10.1186/s40169-017-0181-2] [PMID: 29340951]
[16]
Bolognesi, M.L. Harnessing polypharmacology with medicinal chemistry. ACS Med. Chem. Lett., 2019, 10(3), 273-275.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00039] [PMID: 30891125]
[17]
Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48(21), 6523-6543.
[http://dx.doi.org/10.1021/jm058225d] [PMID: 16220969]
[18]
Pajouhesh, H.; Lenz, G.R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005, 2(4), 541-553.
[http://dx.doi.org/10.1602/neurorx.2.4.541] [PMID: 16489364]
[19]
Prati, F.; Cavalli, A.; Bolognesi, M.L. Navigating the chemical space of multitarget-directed ligands: from hybrids to fragments in alzheimer’s disease. Molecules, 2016, 21(4), 466.
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[20]
Morphy, R.; Rankovic, Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem., 2006, 49(16), 4961-4970.
[http://dx.doi.org/10.1021/jm0603015] [PMID: 16884308]
[21]
Wager, T.T.; Hou, X.; Verhoest, P.R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci., 2010, 1(6), 435-449.
[http://dx.doi.org/10.1021/cn100008c] [PMID: 22778837]
[22]
Donovan, J.M.; Zimmer, M.; Offman, E.; Grant, T.; Jirousek, M. A Novel NF-κB inhibitor, edasalonexent (CAT-1004), in Development as a disease-modifying treatment for patients with duchenne muscular dystrophy: phase 1 safety, pharmacokinetics, and pharmacodynamics in adult subjects. J. Clin. Pharmacol., 2017, 57(5), 627-639.
[http://dx.doi.org/10.1002/jcph.842] [PMID: 28074489]
[23]
Youdim, M.B. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp. Neurobiol., 2013, 22(1), 1-10.
[http://dx.doi.org/10.5607/en.2013.22.1.1] [PMID: 23585716]
[24]
LePage, K.T.; Dickey, R.W.; Gerwick, W.H.; Jester, E.L.; Murray, T.F. On the use of neuro-2a neuroblastoma cells versus intact neurons in primary culture for neurotoxicity studies. Crit. Rev. Neurobiol., 2005, 17(1), 27-50.
[http://dx.doi.org/10.1615/CritRevNeurobiol.v17.i1.20] [PMID: 16307526]
[25]
Uliassi, E.; Peña-Altamira, L.E.; Morales, A.V.; Massenzio, F.; Petralla, S.; Rossi, M.; Roberti, M.; Martinez Gonzalez, L.; Martinez, A.; Monti, B.; Bolognesi, M.L. A focused library of psychotropic analogues with neuroprotective and neuroregenerative potential. ACS Chem. Neurosci., 2019, 10(1), 279-294.
[http://dx.doi.org/10.1021/acschemneuro.8b00242] [PMID: 30253086]
[26]
Nepovimova, E.; Uliassi, E.; Korabecny, J.; Peña-Altamira, L.E.; Samez, S.; Pesaresi, A.; Garcia, G.E.; Bartolini, M.; Andrisano, V.; Bergamini, C.; Fato, R.; Lamba, D.; Roberti, M.; Kuca, K.; Monti, B.; Bolognesi, M.L. Multitarget drug design strategy: Quinone-tacrine hybrids designed to block amyloid-β aggregation and to exert anticholinesterase and antioxidant effects. J. Med. Chem., 2014, 57(20), 8576-8589.
[http://dx.doi.org/10.1021/jm5010804] [PMID: 25259726]
[27]
Miller, T.M.; Johnson, E.M. Jr Metabolic and genetic analyses of apoptosis in potassium/serum-deprived rat cerebellar granule cells. J. Neurosci., 1996, 16(23), 7487-7495.
[http://dx.doi.org/10.1523/JNEUROSCI.16-23-07487.1996] [PMID: 8922404]
[28]
Gameiro, I.; Michalska, P.; Tenti, G.; Cores, Á.; Buendia, I.; Rojo, A.I.; Georgakopoulos, N.D.; Hernández-Guijo, J.M.; Teresa Ramos, M.; Wells, G.; López, M.G.; Cuadrado, A.; Menéndez, J.C.; León, R. Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease. Sci. Rep., 2017, 7, 45701.
[http://dx.doi.org/10.1038/srep45701] [PMID: 28361919]
[29]
Jeřábek, J.; Uliassi, E.; Guidotti, L.; Korábečný, J.; Soukup, O.; Sepsova, V.; Hrabinova, M.; Kuča, K.; Bartolini, M.; Peña-Altamira, L.E.; Petralla, S.; Monti, B.; Roberti, M.; Bolognesi, M.L. Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur. J. Med. Chem., 2017, 127, 250-262.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.048] [PMID: 28064079]
[30]
Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement., 2016, 12(6), 719-732.
[http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]
[31]
Peña-Altamira, E.; Prati, F.; Massenzio, F.; Virgili, M.; Contestabile, A.; Bolognesi, M.L.; Monti, B. Changing paradigm to target microglia in neurodegenerative diseases: From anti-inflammatory strategy to active immunomodulation. Expert Opin. Ther. Targets, 2016, 20(5), 627-640.
[http://dx.doi.org/10.1517/14728222.2016.1121237] [PMID: 26568363]
[32]
Szepesi, Z.; Manouchehrian, O.; Bachiller, S.; Deierborg, T. Bidirectional microglia-neuron communication in health and disease. Front. Cell. Neurosci., 2018, 12, 323.
[http://dx.doi.org/10.3389/fncel.2018.00323] [PMID: 30319362]
[33]
Peña-Altamira, E.; Petralla, S.; Massenzio, F.; Virgili, M.; Bolognesi, M.L.; Monti, B. Nutritional and pharmacological strategies to regulate microglial polarization in cognitive aging and alzheimer’s disease. Front. Aging Neurosci., 2017, 9, 175.
[http://dx.doi.org/10.3389/fnagi.2017.00175] [PMID: 28638339]
[34]
Sousa, C.; Biber, K.; Michelucci, A. Cellular and molecular characterization of microglia: A unique immune cell population. Front. Immunol., 2017, 8, 198.
[http://dx.doi.org/10.3389/fimmu.2017.00198] [PMID: 28303137]
[35]
Roqué, P.J.; Costa, L.G. Co-Culture of neurons and microglia. Curr. Protoc. Toxicol., 2017, 74, 11.24.11-11-11.24.17.
[http://dx.doi.org/10.1002/cptx.32]
[36]
Hovlid, M.L.; Winzeler, E.A. Phenotypic screens in antimalarial drug discovery. Trends Parasitol., 2016, 32(9), 697-707.
[http://dx.doi.org/10.1016/j.pt.2016.04.014] [PMID: 27247245]
[37]
Sykes, M.L.; Avery, V.M. Approaches to protozoan drug discovery: Phenotypic screening. J. Med. Chem., 2013, 56(20), 7727-7740.
[http://dx.doi.org/10.1021/jm4004279] [PMID: 23927763]
[38]
Riss, T.L.; Moravec, R.A.; Niles, A.L.; Duellman, S.; Benink, H.A.; Worzella, T.J.; Minor, L. Cell Viability Assays. Assay Guidance Manual. ; [Internet].. Sittampalam, 2013, pp. 305-335.
[39]
Nwaka, S.; Ramirez, B.; Brun, R.; Maes, L.; Douglas, F.; Ridley, R. Advancing drug innovation for neglected diseases-criteria for lead progression. PLoS Negl. Trop. Dis., 2009, 3(8)e440
[http://dx.doi.org/10.1371/journal.pntd.0000440] [PMID: 19707561]
[40]
Torres-Gómez, H.; Hernández-Núñez, E.; León-Rivera, I.; Guerrero-Alvarez, J.; Cedillo-Rivera, R.; Moo-Puc, R.; Argotte-Ramos, R.; Rodríguez-Gutiérrez, M.C.; Chan-Bacab, M.J.; Navarrete-Vázquez, G. Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids. Bioorg. Med. Chem. Lett., 2008, 18(11), 3147-3151.
[http://dx.doi.org/10.1016/j.bmcl.2008.05.009] [PMID: 18486471]
[41]
Nava-Zuazo, C.; Estrada-Soto, S.; Guerrero-Alvarez, J.; León-Rivera, I.; Molina-Salinas, G.M.; Said-Fernández, S.; Chan-Bacab, M.J.; Cedillo-Rivera, R.; Moo-Puc, R.; Mirón-López, G.; Navarrete-Vazquez, G. Design, synthesis, and in vitro antiprotozoal, antimycobacterial activities of N-2-[(7-chloroquinolin-4-yl)amino]ethylureas. Bioorg. Med. Chem., 2010, 18(17), 6398-6403.
[http://dx.doi.org/10.1016/j.bmc.2010.07.008] [PMID: 20674375]
[42]
Uliassi, E.; Piazzi, L.; Belluti, F.; Mazzanti, A.; Kaiser, M.; Brun, R.; Moraes, C.B.; Freitas-Junior, L.H.; Gul, S.; Kuzikov, M.; Ellinger, B.; Borsari, C.; Costi, M.P.; Bolognesi, M.L. Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections. ChemMedChem, 2018, 13(7), 678-683.
[http://dx.doi.org/10.1002/cmdc.201700786] [PMID: 29451361]
[43]
Zulfiqar, B.; Shelper, T.B.; Avery, V.M. Leishmaniasis drug discovery: Recent progress and challenges in assay development. Drug Discov. Today, 2017, 22(10), 1516-1531.
[http://dx.doi.org/10.1016/j.drudis.2017.06.004] [PMID: 28647378]
[44]
Maurya, S.S.; Khan, S.I.; Bahuguna, A.; Kumar, D.; Rawat, D.S. Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids. Eur. J. Med. Chem., 2017, 129, 175-185.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.024] [PMID: 28222317]
[45]
Lawrenson, A.S.; Cooper, D.L.; O’Neill, P.M.; Berry, N.G. Study of the antimalarial activity of 4-aminoquinoline compounds against chloroquine-sensitive and chloroquine-resistant parasite strains. J. Mol. Model., 2018, 24(9), 237.
[http://dx.doi.org/10.1007/s00894-018-3755-z] [PMID: 30120591]
[46]
Hefnawy, A.; Berg, M.; Dujardin, J.C.; De Muylder, G. Exploiting knowledge on leishmania drug resistance to support the quest for new drugs. Trends Parasitol., 2017, 33(3), 162-174.
[http://dx.doi.org/10.1016/j.pt.2016.11.003] [PMID: 27993477]
[47]
Kloehn, J.; Saunders, E.C.; O’Callaghan, S.; Dagley, M.J.; McConville, M.J. Characterization of metabolically quiescent Leishmania parasites in murine lesions using heavy water labeling. PLoS Pathog., 2015, 11(2)e1004683
[http://dx.doi.org/10.1371/journal.ppat.1004683] [PMID: 25714830]
[48]
Moraes, C.B.; Witt, G.; Kuzikov, M.; Ellinger, B.; Calogeropoulou, T.; Prousis, K.C.; Mangani, S.; Di Pisa, F.; Landi, G.; Iacono, L.D.; Pozzi, C.; Freitas-Junior, L.H.; Dos Santos Pascoalino, B.; Bertolacini, C.P.; Behrens, B.; Keminer, O.; Leu, J.; Wolf, M.; Reinshagen, J.; Cordeiro-da-Silva, A.; Santarem, N.; Venturelli, A.; Wrigley, S.; Karunakaran, D.; Kebede, B.; Pöhner, I.; Müller, W.; Panecka-Hofman, J.; Wade, R.C.; Fenske, M.; Clos, J.; Alunda, J.M.; Corral, M.J.; Uliassi, E.; Bolognesi, M.L.; Linciano, P.; Quotadamo, A.; Ferrari, S.; Santucci, M.; Borsari, C.; Costi, M.P.; Gul, S. Accelerating drug discovery efforts for trypanosomatidic infections using an integrated transnational academic drug discovery platform. SLAS Discov., 2019, 24(3), 346-361.
[http://dx.doi.org/10.1177/2472555218823171] [PMID: 30784368]
[49]
Wang, H.; Zhang, H. Reconsideration of anticholinesterase therapeutic strategies against alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(2), 852-862.
[http://dx.doi.org/10.1021/acschemneuro.8b00391] [PMID: 30521323]
[50]
Bolognesi, M.L.; Matera, R.; Minarini, A.; Rosini, M.; Melchiorre, C. Alzheimer’s disease: New approaches to drug discovery. Curr. Opin. Chem. Biol., 2009, 13(3), 303-308.
[http://dx.doi.org/10.1016/j.cbpa.2009.04.619] [PMID: 19467915]
[51]
Geldenhuys, W.J.; Van der Schyf, C.J. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr. Med. Chem., 2013, 20(13), 1662-1672.
[http://dx.doi.org/10.2174/09298673113209990112] [PMID: 23410161]
[52]
Viayna, E.; Sabate, R.; Muñoz-Torrero, D. Dual inhibitors of β-amyloid aggregation and acetylcholinesterase as multi-target anti-Alzheimer drug candidates. Curr. Top. Med. Chem., 2013, 13(15), 1820-1842.
[http://dx.doi.org/10.2174/15680266113139990139] [PMID: 23931440]
[53]
Dias, K.S.; Viegas, C. Jr Multi-target directed drugs: A modern approach for design of new drugs for the treatment of alzheimer’s disease. Curr. Neuropharmacol., 2014, 12(3), 239-255.
[http://dx.doi.org/10.2174/1570159X1203140511153200] [PMID: 24851088]
[54]
Oset-Gasque, M.J.; Marco-Contelles, J. Alzheimer’s disease, the. alzheimer’s disease, the “one-molecule, one-target” paradigm, and the multitarget directed ligand approach. ACS Chem. Neurosci., 2018, 9(3), 401-403.
[http://dx.doi.org/10.1021/acschemneuro.8b00069] [PMID: 29465220]
[55]
Santos, M.A.; Chand, K.; Chaves, S. Recent progress in repositioning Alzheimer’s disease drugs based on a multitarget strategy. Future Med. Chem., 2016, 8(17), 2113-2142.
[http://dx.doi.org/10.4155/fmc-2016-0103] [PMID: 27774814]
[56]
Lin, H.; Li, Q.; Gu, K.; Zhu, J.; Jiang, X.; Chen, Y.; Sun, H. Therapeutic agents in alzheimer’s disease through a multi-targetdirected ligands strategy: Recent progress based on tacrine core. Curr. Top. Med. Chem., 2017, 17(27), 3000-3016.
[http://dx.doi.org/10.2174/1568026617666170717114944] [PMID: 28714419]
[57]
Spilovska, K.; Korabecny, J.; Nepovimova, E.; Dolezal, R.; Mezeiova, E.; Soukup, O.; Kuca, K. Multitarget tacrine hybrids with neuroprotective properties to confront alzheimer’s disease. Curr. Top. Med. Chem., 2017, 17(9), 1006-1026.
[http://dx.doi.org/10.2174/1568026605666160927152728] [PMID: 27697055]
[58]
de Freitas Silva, M.; Dias, K.S.T.; Gontijo, V.S.; Ortiz, C.J.C.; Viegas, C. Jr Multi-target directed drugs as a modern approach for drug design towards Alzheimer’s disease: An update. Curr. Med. Chem., 2018, 25(29), 3491-3525.
[http://dx.doi.org/10.2174/0929867325666180111101843] [PMID: 29332563]
[59]
Minarini, A.; Milelli, A.; Simoni, E.; Rosini, M.; Bolognesi, M.L.; Marchetti, C.; Tumiatti, V. Multifunctional tacrine derivatives in Alzheimer’s disease. Curr. Top. Med. Chem., 2013, 13(15), 1771-1786.
[http://dx.doi.org/10.2174/15680266113139990136] [PMID: 23931443]
[60]
Agis-Torres, A.; Sölhuber, M.; Fernandez, M.; Sanchez-Montero, J.M. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for alzheimer’s disease. Curr. Neuropharmacol., 2014, 12(1), 2-36.
[http://dx.doi.org/10.2174/1570159X113116660047] [PMID: 24533013]
[61]
Soler-López, M.; Badiola, N.; Zanzoni, A.; Aloy, P. Towards Alzheimer’s root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction. Hypothetical role of the adapter protein ECSIT in familial and sporadic Alzheimer’s disease pathogenesis. BioEssays, 2012, 34(7), 532-541.
[http://dx.doi.org/10.1002/bies.201100193] [PMID: 22513506]
[62]
Cavalli, A.; Bolognesi, M.L.; Capsoni, S.; Andrisano, V.; Bartolini, M.; Margotti, E.; Cattaneo, A.; Recanatini, M.; Melchiorre, C. A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew. Chem. Int. Ed. Engl., 2007, 46(20), 3689-3692.
[http://dx.doi.org/10.1002/anie.200700256] [PMID: 17397121]
[63]
Tumiatti, V.; Minarini, A.; Bolognesi, M.L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine derivatives and Alzheimer’s disease. Curr. Med. Chem., 2010, 17(17), 1825-1838.
[http://dx.doi.org/10.2174/092986710791111206] [PMID: 20345341]
[64]
Bolognesi, M.L.; Chiriano, G.; Bartolini, M.; Mancini, F.; Bottegoni, G.; Maestri, V.; Czvitkovich, S.; Windisch, M.; Cavalli, A.; Minarini, A.; Rosini, M.; Tumiatti, V.; Andrisano, V.; Melchiorre, C. Synthesis of monomeric derivatives to probe memoquin’s bivalent interactions. J. Med. Chem., 2011, 54(24), 8299-8304.
[http://dx.doi.org/10.1021/jm200691d] [PMID: 22054058]
[65]
Galdeano, C.; Viayna, E.; Sola, I.; Formosa, X.; Camps, P.; Badia, A.; Clos, M.V.; Relat, J.; Ratia, M.; Bartolini, M.; Mancini, F.; Andrisano, V.; Salmona, M.; Minguillón, C.; González-Muñoz, G.C.; Rodríguez-Franco, M.I.; Bidon-Chanal, A.; Luque, F.J.; Muñoz-Torrero, D. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer’s and prion diseases. J. Med. Chem., 2012, 55(2), 661-669.
[http://dx.doi.org/10.1021/jm200840c] [PMID: 22185619]
[66]
Soukup, O.; Jun, D.; Zdarova-Karasova, J.; Patocka, J.; Musilek, K.; Korabecny, J.; Krusek, J.; Kaniakova, M.; Sepsova, V.; Mandikova, J.; Trejtnar, F.; Pohanka, M.; Drtinova, L.; Pavlik, M.; Tobin, G.; Kuca, K. A resurrection of 7-MEOTA: A comparison with tacrine. Curr. Alzheimer Res., 2013, 10(8), 893-906.
[http://dx.doi.org/10.2174/1567205011310080011] [PMID: 24093535]
[67]
Romero, A.; Cacabelos, R.; Oset-Gasque, M.J.; Samadi, A.; Marco-Contelles, J. Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2013, 23(7), 1916-1922.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.017] [PMID: 23481643]
[68]
Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Melchiorre, C. From dual binding site acetylcholinesterase inhibitors to multi-target-directed ligands (MTDLs): A step forward in the treatment of Alzheimer’s disease. Mini Rev. Med. Chem., 2008, 8(10), 960-967.
[http://dx.doi.org/10.2174/138955708785740652] [PMID: 18782050]
[69]
Rampa, A.; Belluti, F.; Gobbi, S.; Bisi, A. Hybrid-based multi-target ligands for the treatment of Alzheimer’s disease. Curr. Top. Med. Chem., 2011, 11(22), 2716-2730.
[http://dx.doi.org/10.2174/156802611798184409] [PMID: 22039875]
[70]
Muñoz-Torrero, D.; Camps, P. Dimeric and hybrid anti-Alzheimer drug candidates. Curr. Med. Chem., 2006, 13(4), 399-422.
[http://dx.doi.org/10.2174/092986706775527974] [PMID: 16475930]
[71]
Cavalli, A.; Bolognesi, M.L. Neglected tropical diseases: Multi-target-directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania. J. Med. Chem., 2009, 52(23), 7339-7359.
[http://dx.doi.org/10.1021/jm9004835] [PMID: 19606868]
[72]
Njogu, P.M.; Chibale, K. Recent developments in rationally designed multitarget antiprotozoan agents. Curr. Med. Chem., 2013, 20(13), 1715-1742.
[http://dx.doi.org/10.2174/0929867311320130010] [PMID: 23410169]
[73]
Herricks, J.R.; Hotez, P.J.; Wanga, V.; Coffeng, L.E.; Haagsma, J.A.; Basáñez, M.G.; Buckle, G.; Budke, C.M.; Carabin, H.; Fèvre, E.M.; Fürst, T.; Halasa, Y.A.; King, C.H.; Murdoch, M.E.; Ramaiah, K.D.; Shepard, D.S.; Stolk, W.A.; Undurraga, E.A.; Stanaway, J.D.; Naghavi, M.; Murray, C.J.L. The global burden of disease study 2013: What does it mean for the NTDs? PLoS Negl. Trop. Dis., 2017, 11(8)e0005424
[http://dx.doi.org/10.1371/journal.pntd.0005424] [PMID: 28771480]
[74]
Watt, P.M. Phenotypic screening of phylomer peptide libraries derived from genome fragments to identify and validate new targets and therapeutics. Future Med. Chem., 2009, 1(2), 257-265.
[http://dx.doi.org/10.4155/fmc.09.28] [PMID: 21425969]
[75]
Cavalli, A.; Lizzi, F.; Bongarzone, S.; Belluti, F.; Piazzi, L.; Bolognesi, M.L. Complementary medicinal chemistry-driven strategies toward new antitrypanosomal and antileishmanial lead drug candidates. FEMS Immunol. Med. Microbiol., 2010, 58(1), 51-60.
[http://dx.doi.org/10.1111/j.1574-695X.2009.00615.x] [PMID: 19845762]
[76]
Horton, D.A.; Bourne, G.T.; Smythe, M.L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures. Chem. Rev., 2003, 103(3), 893-930.
[http://dx.doi.org/10.1021/cr020033s] [PMID: 12630855]
[77]
Bräse, S. Privileged scaffolds in medicinal chemistry: Design, synthesis, evaluation, (1st ed. ),; Royal Society of Chemistry: London, U.K., 2015.
[http://dx.doi.org/10.1039/9781782622246]
[78]
Uliassi, E.; Piazzi, L.; Belluti, F.; Kaiser, M.; Brun, R.; Gul, S.; Ellinger, B.; Moraes, C.B.; Freitas-Junior, L.H.; Borsari, C.; Costi, M.P.; Bolognesi, M.L. Design, synthesis and structure—activity relationships of a phenotypic small library against protozoan infections. Proceedings, 2017, 1(6), 648.
[http://dx.doi.org/10.3390/proceedings1060648]
[79]
Guantai, E.M.; Ncokazi, K.; Egan, T.J.; Gut, J.; Rosenthal, P.J.; Smith, P.J.; Chibale, K. Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds. Bioorg. Med. Chem., 2010, 18(23), 8243-8256.
[http://dx.doi.org/10.1016/j.bmc.2010.10.009] [PMID: 21044845]
[80]
Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem., 2011, 18(10), 1464-1475.
[http://dx.doi.org/10.2174/092986711795328355] [PMID: 21428895]
[81]
Singh, M.; Kaur, M.; Chadha, N.; Silakari, O. Hybrids: A new paradigm to treat Alzheimer’s disease. Mol. Divers., 2016, 20(1), 271-297.
[http://dx.doi.org/10.1007/s11030-015-9628-9] [PMID: 26328942]
[82]
Koeberle, A.; Werz, O. Multi-target approach for natural products in inflammation. Drug Discov. Today, 2014, 19(12), 1871-1882.
[http://dx.doi.org/10.1016/j.drudis.2014.08.006] [PMID: 25172801]
[83]
Lu, C.; Guo, Y.; Li, J.; Yao, M.; Liao, Q.; Xie, Z.; Li, X. Design, synthesis, and evaluation of resveratrol derivatives as Aß(1-42) aggregation inhibitors, antioxidants, and neuroprotective agents. Bioorg. Med. Chem. Lett., 2012, 22(24), 7683-7687.
[http://dx.doi.org/10.1016/j.bmcl.2012.09.105] [PMID: 23127891]
[84]
Turner, R.S.; Thomas, R.G.; Craft, S.; van Dyck, C.H.; Mintzer, J.; Reynolds, B.A.; Brewer, J.B.; Rissman, R.A.; Raman, R.; Aisen, P.S. Alzheimer’s Disease Cooperative Study. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology, 2015, 85(16), 1383-1391.
[http://dx.doi.org/10.1212/WNL.0000000000002035] [PMID: 26362286]
[85]
Bishayee, A.; Darvesh, A.S.; Politis, T.; McGory, R. Resveratrol and liver disease: from bench to bedside and community. Liver Int., 2010, 30(8), 1103-1114.
[http://dx.doi.org/10.1111/j.1478-3231.2010.02295.x] [PMID: 20557453]
[86]
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, 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[87]
Colton, C.A.; Mott, R.T.; Sharpe, H.; Xu, Q.; Van Nostrand, W.E.; Vitek, M.P. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation, 2006, 3(1), 27.
[http://dx.doi.org/10.1186/1742-2094-3-27] [PMID: 17005052]
[88]
Boche, D.; Perry, V.H.; Nicoll, J.A. Review: activation patterns of microglia and their identification in the human brain. Neuropathol. Appl. Neurobiol., 2013, 39(1), 3-18.
[http://dx.doi.org/10.1111/nan.12011] [PMID: 23252647]
[89]
Pierce, R.J.; MacDougall, J.; Leurs, R.; Costi, M.P. The future of drug development for neglected tropical diseases: How the european commission can continue to make a difference. Trends Parasitol., 2017, 33(8), 581-583.
[http://dx.doi.org/10.1016/j.pt.2017.04.007] [PMID: 28529130]
[90]
Franco, J.R.; Simarro, P.P.; Diarra, A.; Jannin, J.G. Epidemiology of human African trypanosomiasis. Clin. Epidemiol., 2014, 6, 257-275.
[http://dx.doi.org/10.2147/CLEP.S39728] [PMID: 25125985]
[91]
Franco, J.R.; Cecchi, G.; Priotto, G.; Paone, M.; Diarra, A.; Grout, L.; Simarro, P.P.; Zhao, W.; Argaw, D. Monitoring the elimination of human African trypanosomiasis: Update to 2016. PLoS Negl. Trop. Dis., 2018, 12(12)e0006890
[http://dx.doi.org/10.1371/journal.pntd.0006890] [PMID: 30521525]
[92]
Baker, C.H.; Welburn, S.C. The long wait for a new drug for human african trypanosomiasis. Trends Parasitol., 2018, 34(10), 818-827.
[http://dx.doi.org/10.1016/j.pt.2018.08.006] [PMID: 30181071]
[93]
Simarro, P.P.; Jannin, J.; Cattand, P. Eliminating human African trypanosomiasis: Where do we stand and what comes next? PLoS Med., 2008, 5(2)e55
[http://dx.doi.org/10.1371/journal.pmed.0050055] [PMID: 18303943]
[94]
Cerone, M.; Uliassi, E.; Prati, F.; Ebiloma, G.U.; Lemgruber, L.; Bergamini, C.; Watson, D.G. de A M Ferreira, T.; Roth Cardoso, G.S.H.; Soares Romeiro, L.A.; de Koning, H.P.; Bolognesi, M.L., Discovery of sustainable drugs for neglected tropical diseases: cashew nut shell liquid (CNSL)-based hybrids target mitochondrial function and atp production in Trypanosoma brucei. ChemMedChem, 2019, Vol.14(6), 621-635.
[http://dx.doi.org/10.1002/cmdc.201800790]
[95]
Lutumba, P.; Makieya, E.; Shaw, A.; Meheus, F.; Boelaert, M. Human African trypanosomiasis in a rural community, Democratic Republic of Congo. Emerg. Infect. Dis., 2007, 13(2), 248-254.
[http://dx.doi.org/10.3201/eid1302.060075] [PMID: 17479887]
[96]
Dugmore, T.I.J.; Clark, J.H.; Bustamante, J.; Houghton, J.A.; Matharu, A.S. Valorisation of biowastes for the production of green materials using chemical methods. Top. Curr. Chem. (Cham), 2017, 375(2), 46.
[http://dx.doi.org/10.1007/s41061-017-0133-8] [PMID: 28374283]
[97]
Hamad, F.B.; Mubofu, E.B. Potential biological applications of bio-based anacardic acids and their derivatives. Int. J. Mol. Sci., 2015, 16(4), 8569-8590.
[http://dx.doi.org/10.3390/ijms16048569] [PMID: 25894225]
[98]
Balachandran, V.S.; Jadhav, S.R.; Vemula, P.K.; John, G. Recent advances in cardanol chemistry in a nutshell: from a nut to nanomaterials. Chem. Soc. Rev., 2013, 42(2), 427-438.
[http://dx.doi.org/10.1039/C2CS35344J] [PMID: 23114456]
[99]
Bolognesi, M.L.; Lizzi, F.; Perozzo, R.; Brun, R.; Cavalli, A. Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity. Bioorg. Med. Chem. Lett., 2008, 18(7), 2272-2276.
[http://dx.doi.org/10.1016/j.bmcl.2008.03.009] [PMID: 18353643]
[100]
Pieretti, S.; Haanstra, J.R.; Mazet, M.; Perozzo, R.; Bergamini, C.; Prati, F.; Fato, R.; Lenaz, G.; Capranico, G.; Brun, R.; Bakker, B.M.; Michels, P.A.; Scapozza, L.; Bolognesi, M.L.; Cavalli, A. Naphthoquinone derivatives exert their antitrypanosomal activity via a multi-target mechanism. PLoS Negl. Trop. Dis., 2013, 7(1)e2012
[http://dx.doi.org/10.1371/journal.pntd.0002012] [PMID: 23350008]
[101]
Pereira, J.M.; Severino, R.P.; Vieira, P.C.; Fernandes, J.B.; da Silva, M.F.; Zottis, A.; Andricopulo, A.D.; Oliva, G.; Corrêa, A.G. Anacardic acid derivatives as inhibitors of glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi. Bioorg. Med. Chem., 2008, 16(19), 8889-8895.
[http://dx.doi.org/10.1016/j.bmc.2008.08.057] [PMID: 18789702]
[102]
Delespaux, V.; de Koning, H.P. Drugs and drug resistance in African trypanosomiasis. Drug Resist. Updat., 2007, 10(1-2), 30-50.
[http://dx.doi.org/10.1016/j.drup.2007.02.004] [PMID: 17409013]
[103]
Bottegoni, G.; Favia, A.D.; Recanatini, M.; Cavalli, A. The role of fragment-based and computational methods in polypharmacology. Drug Discov. Today, 2012, 17(1-2), 23-34.
[http://dx.doi.org/10.1016/j.drudis.2011.08.002] [PMID: 21864710]
[104]
Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.; Hirth, P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov., 2012, 11(11), 873-886.
[http://dx.doi.org/10.1038/nrd3847] [PMID: 23060265]
[105]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630]
[106]
Davis, B.J.; Roughley, S.D. Fragment-based Lead Discovery. Ann. Rep. Med. Chem., 2017, 50, 371-439.
[107]
Prati, F.; De Simone, A.; Bisignano, P.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Favia, A.D.; Bottegoni, G.; Martinez, A.; Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3β inhibitors. Angew. Chem. Int. Ed. Engl., 2015, 54(5), 1578-1582.
[http://dx.doi.org/10.1002/anie.201410456] [PMID: 25504761]
[108]
Prati, F.; De Simone, A.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Bertozzi, S.M.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Sabatino, P.; Bottegoni, G.; Martinez, A.; Cavalli, A.; Bolognesi, M.L. 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease. ACS Chem. Neurosci., 2015, 6(10), 1665-1682.
[http://dx.doi.org/10.1021/acschemneuro.5b00121] [PMID: 26171616]
[109]
Vassar, R.; Citron, M. Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron, 2000, 27(3), 419-422.
[http://dx.doi.org/10.1016/S0896-6273(00)00051-9] [PMID: 11055423]
[110]
Ghosh, A.K.; Cárdenas, E.L.; Osswald, H.L. The design, development, and evaluation of BACE1 inhibitors for the treatment of alzheimer’s disease. Alzheimer’s Disease II., 2017, 27-85.
[http://dx.doi.org/10.1007/7355_2016_16]
[111]
Avila, J.; Wandosell, F.; Hernández, F. Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev. Neurother., 2010, 10(5), 703-710.
[http://dx.doi.org/10.1586/ern.10.40] [PMID: 20420491]
[112]
Llorens-Martín, M.; Jurado, J.; Hernández, F.; Avila, J. GSK-3β, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci., 2014, 7, 46.
[http://dx.doi.org/10.3389/fnmol.2014.00046] [PMID: 24904272]
[113]
Morphy, R.; Rankovic, Z. Fragments, network biology and designing multiple ligands. Drug Discov. Today, 2007, 12(3-4), 156-160.
[http://dx.doi.org/10.1016/j.drudis.2006.12.006] [PMID: 17275736]
[114]
Zheng, H.; Fridkin, M.; Youdim, M. From single target to multitarget/network therapeutics in Alzheimer’s therapy. Pharmaceuticals (Basel), 2014, 7(2), 113-135.
[http://dx.doi.org/10.3390/ph7020113] [PMID: 24463342]
[115]
Prati, F.; Bottegoni, G.; Bolognesi, M.L.; Cavalli, A. BACE-1 Inhibitors: From recent single-target molecules to multitarget compounds for alzheimer’s disease. J. Med. Chem., 2018, 61(3), 619-637.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00393] [PMID: 28749667]

Rights & Permissions Print Cite
Article Metrics
83
5
1
1
© 2024 Bentham Science Publishers | Privacy Policy