Multi-Target Hybrid Drugs: A Promising Approach for Treating Alzheimer's, Neurological Diseases, Diabetes, and Cancer
الموضوعات :
Armineh Rezagholi Lalani
1
,
Fariba Ebrahimbabaie
2
,
Mohsen Sojoudi
3
,
Nima Pouyani
4
,
Marzie Salari Sharifabad
5
,
Fatemeh Fakhari
6
,
Sepideh Rezaei
7
1 - Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
2 - Family Research Institute, Shahid Beheshti University, Tehran, Iran
3 - Department Operations Research (OR), Management Sciences at Ferdowsi University of Mashhad, Mashhad, Iran
4 - Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
5 - Department of Pharmacy, International Campus, School of Pharmacy, Tehran University of Medical Science, Tehran, Iran
6 - Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
7 - Department of Chemistry, University of Houston, 3585 Cullen Blvd., Fleming Bldg. Rm 112, Houston, TX 77204-5003, USA
الکلمات المفتاحية: Acridine, Tacrine, Multi-factorial diseases, Multi-target drugs,
ملخص المقالة :
Multi-target drugs are a class of hybrid compounds that can act on multiple targets and diseases simultaneously. These drugs have the potential to treat a range of disorders including Alzheimer's disease, diabetes, and cancer. This review aims to assess the efficacy of acridine- and tacrine-based multi-target hybrid drugs for the treatment of various diseases. In December 2022, a systematic literature search was conducted using "acridine," "tacrine," "multi-target agent, "and "multi-factorial diseases" along with their synonyms. According to the findings, acridine-based conjugates exhibited anti-cancer and anti-diabetic properties by directly inhibiting α-Glucosidase and α-Amylase, and by binding to DNA, topoisomerases, histone deacetylase, and poly (ADP-ribose) polymerase. The results suggest that acridine- and tacrine-based hybrid complexes have the potential to serve as promising multi-target agents for the treatment of Alzheimer's disease, neurological disorders, diabetes, and cancer. Overall, these compounds offer a new approach to drug development by targeting multiple disease pathways with a single agent. In conclusion, the use of multi-target drugs could potentially lead to improved therapeutic outcomes with fewer side effects, making them a promising area of research for the treatment of complex diseases. Keywords for this review include acridine, tacrine, multi-factorial diseases, and multi-target drugs.
1. Prasher P., Sharma M., 2018. Medicinal chemistry of acridine and its analogues. Medchemcomm. 9(10), 1589-1618.
2. Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gøtzsche P.C., Ioannidis J.P.A., Clarke M., Devereaux P.J., Kleijnen J., Moher D., 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 62(10), e1-e34.
3. Xie S.S., Wang X., Jiang N., Yu W., Wang K.D., Lan J.S., Li Z.R., Kong L.Y., 2015. Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease. Eur J Med Chem. 95, 153-165.
4. Lalani A.R., Pouyani N.R., Askari A., Tavajohi S., Akbari S., Jafarzadeh E., 2023. Food Additives, Benefits, and Side Effects: A Review Article. Journal of Chemical Health Risks. [In Press]
5. Xu A., He F., Zhang X., Li X., Ran Y., Wei C., James Chou C., Zhang R., Wu J., 2020. Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation. Bioorg Chem. 98, 103721.
6. Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gøtzsche P.C., Ioannidis J.P.A., Clarke M., Devereaux P.J., Kleijnen J., Moher D., 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 62(10), e1-e34.
7. Tseng H.J., Lin M.H., Shiao Y.J., Yang Y.C., Chu J.C., Chen C.Y., Chen Y.Y., Lin T.E., Su C.J., Pan S.L., Chen L.C., Wang C.Y., Hsu K.C., Huang W.J., 2020. Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease. Eur J Med Chem. 192, 112193.
8. Riazimontazer E., Sadeghpour H., Nadri H., Sakhteman A., Tüylü Küçükkılınç T., Miri R., Edraki N., 2019. Design, synthesis and biological activity of novel
tacrine-isatin Schiff base hybrid derivatives. Bioorg Chem. 89, 103006.
9. Chalupova K., Korabecny J., Bartolini M., Monti B., Lamba D., Caliandro R., Pesaresi A., Brazzolotto X., Gastellier A. J., Nachon F., Pejchal J., Jarosova M., Hepnarova V., Jun D., Hrabinova M., Dolezal R., Zdarova Karasova J., Mzik M., Kristofikova Z., Misik J., Muckova L., Jost P., Soukup O., Benkova M., Setnicka V., Habartova L., Chvojkova M., Kleteckova L., Vales K., Mezeiova E., Uliassi E., Valis M., Nepovimova E., Bolognesi M. L., Kuca K., 2019. Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease. Eur J Med Chem. 168, 491-514.
10. Rajeshwari R., Chand K., Candeias E., Cardoso S.M., Chaves S., Santos M.A., 2019. New Multitarget Hybrids Bearing Tacrine and Phenylbenzothiazole Motifs as Potential Drug Candidates for Alzheimer's Disease. Molecules. 24(3), 587. https:// doi. org/ 10.3390 / molecules24030587
11. Oukoloff K., Coquelle N., Bartolini M., Naldi M., Le Guevel R., Bach S., Josselin B., Ruchaud S., Catto M., Pisani L., Denora N., Iacobazzi R.M., Silman I., Sussman J.L., Buron F., Colletier J.P., Jean L., Routier S., Renard P.Y., 2019. Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3. Eur J Med Chem. 168, 58-77.
12. Riazimontazer E., Sadeghpour H., Nadri H., Sakhteman A., Tuylu Kucukkilinc T., Miri R., Edraki N., 2019. Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorg Chem. 89, 103006.
13. Chioua M., Buzzi E., Moraleda I., Iriepa I., Maj M., Wnorowski A., Giovannini C., Tramarin A., Portali F., Ismaili L., Lopez-Alvarado P., Bolognesi M.L., Jozwiak K., Menendez J.C., Marco-Contelles J., Bartolini M., 2018. Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease. Eur J Med Chem. 155, 839-846.
14. Chen Y., Zhu J., Mo J., Yang H., Jiang X., Lin H., Gu K., Pei Y., Wu L., Tan R., Hou J., Chen J., Lv Y., Bian Y., Sun H., 2018. Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. J Enzyme Inhib Med Chem. 33(1), 290-302.
15. Chand K., Rajeshwari, Candeias E., Cardoso S. M., Chaves S., Santos M.A., 2018. Tacrine-deferiprone hybrids as multi-target-directed metal chelators against Alzheimer's disease: a two-in-one drug. Metallomics. 10(10), 1460-1475.
16. Hamulakova S., Janovec L., Soukup O., Jun D., Janockova J., Hrabinova M., Sepsova V., Kuca K., 2018. Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier. Curr Alzheimer Res. 15(12), 1096-1105.
17. Hiremathad A., Keri R.S., Esteves A.R., Cardoso S.M., Chaves S., Santos M.A., 2018. Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease. Eur J Med Chem. 148, 255-267.
18. Liu W., Wang H., Li X., Xu Y., Zhang J., Wang W., Gong Q., Qiu X., Zhu J., Mao F., Zhang H., Li J., 2018. Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment. Bioorg Med Chem. 26(12), 3117-3125.
19. Yuan Z., Chen S., Chen C., Chen J., Dai Q., Gao C., Jiang Y., 2017. Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy. Eur J Med Chem. 138, 1135-1146.
20. Gazova Z., Soukup O., Sepsova V., Siposova K., Drtinova L., Jost P., Spilovska K., Korabecny J., Nepovimova E., Fedunova D., Horak M., Kaniakova M., Wang Z. J., Hamouda A. K., Kuca K., 2017. Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment. Biochim Biophys Acta Mol Basis Dis. 1863(2), 607-619.
21. Li X., Wang H., Xu Y., Liu W., Gong Q., Wang W., Qiu X., Zhu J., Mao F., Zhang H., Li J., 2017. Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation. ACS Chem Neurosci. 8(12), 2708-2721.
22. Jerabek J., Uliassi E., Guidotti L., Korabecny J., Soukup O., Sepsova V., Hrabinova M., Kuca K., Bartolini M., Pena-Altamira L.E., Petralla S., Monti B., Roberti M., Bolognesi M.L., 2017. Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease. Eur J Med Chem. 127, 250-262.
23. Czarnecka K., Chufarova N., Halczuk K., Maciejewska K., Girek M., Skibinski R., Jonczyk J., Bajda M., Kabzinski J., Majsterek I., Szymanski P., 2018. Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment. Eur J Med Chem. 145, 760-769.
24. Zhang W., Zhang B., Yang T., Wang N., Gao C., Tan C., Liu H., Jiang Y., 2016. Synthesis and antiproliferative activity of 9-benzylamino-6-chloro-2-methoxy-acridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors. Eur J Med Chem. 116, 59-70.
25. Chand K., Alsoghier H. M., Chaves S., Santos M.A., 2016. Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti-Alzheimer's agents: AChE inhibition, antioxidant activity and metal chelating capacity. J Inorg Biochem. 163, 266-277.
26. Zha X., Lamba D., Zhang L., Lou Y., Xu C., Kang D., Chen L., Xu Y., De Simone A., Samez S., Pesaresi A., Stojan J., Lopez M. G., Egea J., Andrisano V., Bartolini M., 2016. Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography. J Med Chem. 59(1), 114-131.
27. Wieckowska A., Kolaczkowski M., Bucki A., Godyn J., Marcinkowska M., Wieckowski K., Zareba P., Siwek A., Kazek G., Gluch-Lutwin M., Mierzejewski P., Bienkowski P., Sienkiewicz-Jarosz H., Knez D., Wichur T., Gobec S., Malawska B., 2016. Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation. Eur J Med Chem. 124, 63-81.
28. Benek O., Soukup O., Pasdiorova M., Hroch L., Sepsova V., Jost P., Hrabinova M., Jun D., Kuca K., Zala D., Ramsay R. R., Marco-Contelles J., Musilek K., 2016. Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease. Chem Med Chem. 11(12), 1264-1269.
29. Zhang C., Du Q.Y., Chen L.D., Wu W.H., Liao S.Y., Yu L.H., Liang X.T., 2016. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease. Eur J Med Chem. 116, 200-209.
30. Cui Z., Li X., Li L., Zhang B., Gao C., Chen Y., Tan C., Liu H., Xie W., Yang T., Jiang Y., 2016. Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment. Bioorg Med Chem. 24 (2), 261-269.
31. Najafi Z., Saeedi M., Mahdavi M., Sabourian R., Khanavi M., Tehrani M. B., Moghadam F. H., Edraki N., Karimpor-Razkenari E., Sharifzadeh M., Foroumadi A., Shafiee A., Akbarzadeh T., 2016. Design and synthesis of novel anti-Alzheimer’s agents: Acridine-chromenone and quinoline-chromenone hybrids. Bioorg Chem. 67, 84-94.
32. Nepovimova E., Korabecny J., Dolezal R., Babkova K., Ondrejicek A., Jun D., Sepsova V., Horova A., Hrabinova M., Soukup O., Bukum N., Jost P., Muckova L., Kassa J., Malinak D., Andrs M., Kuca K., 2015. Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity. J Med Chem. 58 (22), 8985-9003.
33. Benchekroun M., Bartolini M., Egea J., Romero A., Soriano E., Pudlo M., Luzet V., Andrisano V., Jimeno M.L., Lopez M. G., Wehle S., Gharbi T., Refouvelet B., de Andres L., Herrera-Arozamena C., Monti B., Bolognesi M.L., Rodriguez-Franco M.I., Decker M., Marco-Contelles J., Ismaili L., 2015. Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids. Chem Med Chem. 10(3), 523-539.
34. Digiacomo M., Chen Z., Wang S., Lapucci A., Macchia M., Yang X., Chu J., Han Y., Pi R., Rapposelli S., 2015. Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg Med Chem Lett. 25(4), 807-810.
35. Li B., Gao C.M., Sun Q.S., Li L.L., Tan C.Y., Liu H.X., Jiang Y.Y., 2014. Novel synthetic acridine-based derivatives as topoisomerase I inhibitors. Chinese Chem Let. 25(7), 1021-1024.
36. Lan J.S., Xie S.S., Li S.Y., Pan L.F., Wang X.B., Kong L.Y., 2014. Design, synthesis and evaluation of novel tacrine-(beta-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. Bioorg Med Chem. 22(21), 6089-6104.
37. Li S.Y., Jiang N., Xie S.S., Wang K.D., Wang X.B., Kong L.Y., 2014. Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease. Org Biomol Chem. 12(5), 801-814.
38. Sun Q., Peng D.Y., Yang S.G., Zhu X.L., Yang W.C., Yang G.F., 2014. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Abeta aggregation, and beta-secretase. Bioorg Med Chem. 22(17), 4784-4791.
39. Chen Y., Sun J., Peng S., Liao H., Zhang Y., Lehmann J., 2013. Tacrine-flurbiprofen hybrids as multifunctional drug candidates for the treatment of Alzheimer's disease. Arch Pharm (Weinheim). 346(12), 865-871.
40. Keri R.S., Quintanova C., Marques S.M., Esteves A.R., Cardoso S.M., Santos M.A., 2013. Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg Med Chem. 21(15), 4559-4569.
41. 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., Minguillon C., Gonzalez-Munoz G.C., Rodriguez-Franco M.I., Bidon-Chanal A., Luque F.J., Munoz-Torrero D., 2012. Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases. J Med Chem. 55(2), 661-669.
42. Chao X., He X., Yang Y., Zhou X., Jin M., Liu S., Cheng Z., Liu P., Wang Y., Yu J., Tan Y., Huang Y., Qin J., Rapposelli S., Pi R., 2012. Design, synthesis and pharmacological evaluation of novel tacrine-caffeic acid hybrids as multi-targeted compounds against Alzheimer's disease. Bioorg Med Chem Lett. 22(20), 6498-6502.
43. Munoz-Torrero D., Pera M., Relat J., Ratia M., Galdeano C., Viayna E., Sola I., Formosa X., Camps P., Badia A., Clos M. V., 2012. Expanding the multipotent profile of huprine-tacrine heterodimers as disease-modifying anti-Alzheimer agents. Neurodegener Dis. 10(1-4), 96-99.
44. Minarini A., Milelli A., Tumiatti V., Rosini M., Simoni E., Bolognesi M.L., Andrisano V., Bartolini M., Motori E., Angeloni C., Hrelia S., 2012. Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment. Neuropharmacology. 62(2), 997-1003.
45. Pereira J.D., Caricati-Neto A., Miranda-Ferreira R., Smaili S.S., Godinho R.O., de los Rios C., Leon R., Villaroya M., Samadi A., Marco-Contelles J., Jurkiewicz N. H., Garcia A. G., Jurkiewicz A., 2011. Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity. Eur J Pharmacol. 660(2-3), 411-419.
46. Rizzo S., Bisi A., Bartolini M., Mancini F., Belluti F., Gobbi S., Andrisano V., Rampa A., 2011. Multi-target strategy to address Alzheimer's disease: design, synthesis and biological evaluation of new tacrine-based dimers. Eur J Med Chem. 46(9), 4336-4343.
47. Ouberai M., Brannstrom K., Vestling M., Olofsson A., Dumy P., Chierici S., Garcia J., 2011. Clicked tacrine conjugates as acetylcholinesterase and beta-amyloid directed compounds. Org Biomol Chem. 9(4), 1140-1147.
48. Luan X., Gao C., Zhang N., Chen Y., Sun Q., Tan C., Liu H., Jin Y., Jiang Y., 2011. Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and Src kinase inhibitors. Bioorg Med Chem. 19(11), 3312-3319.
49. Tang H., Zhao L.Z., Zhao H.T., Huang S.L., Zhong S.M., Qin J.K., Chen Z.F., Huang Z.S., Liang H., 2011. Hybrids of oxoisoaporphine-tacrine congeners: novel acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation inhibitors. Eur J Med Chem. 46(10), 4970-4979.
50. Fernandez-Bachiller M.I., Perez C., Campillo N.E., Paez J.A., Gonzalez-Munoz G.C., Usan P., Garcia-Palomero E., Lopez M.G., Villarroya M., Garcia A.G., Martinez A., Rodriguez-Franco M.I., 2009. Tacrine-melatonin hybrids as multifunctional agents for Alzheimer's disease, with cholinergic, antioxidant, and neuroprotective properties. Chem Med Chem. 4 (5), 828-841.
51. Vispe S., Vandenberghe I., Robin M., Annereau J.P., Creancier L., Pique V., Galy J.P., Kruczynski A., Barret J.M., Bailly C., 2007. Novel tetra-acridine derivatives as dual inhibitors of topoisomerase II and the human proteasome. Biochem Pharmacol. 73(12), 1863-1872.
52. Bolognesi M.L., Cavalli A., Valgimigli L., Bartolini M., Rosini M., Andrisano V., Recanatini M., Melchiorre C., 2007. Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer's disease. J Med Chem. 50(26), 6446-6449.
53. Camps P., Formosa X., Munoz-Torrero D., Petrignet J., Badia A., Clos M.V., 2005. Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: subnanomolar dual binding site acetylcholinesterase inhibitors. J Med Chem. 48(6), 1701-1704.
54. Dorronsoro I., Alonso D., Castro A., del Monte M., Garcia-Palomero E., Martinez A., 2005. Synthesis and biological evaluation of tacrine-thiadiazolidinone hybrids as dual acetylcholinesterase inhibitors. Arch Pharm (Weinheim). 338(1), 18-23.
55. Munoz-Ruiz P., Rubio L., Garcia-Palomero E., Dorronsoro I., del Monte-Millan M., Valenzuela R., Usan P., de Austria C., Bartolini M., Andrisano V., Bidon-Chanal A., Orozco M., Luque F.J., Medina M., Martinez A., 2005. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. J Med Chem. 48(23), 7223-7233.
56. Gamage S.A., Spicer J.A., Atwell G.J., Finlay G.J., Baguley B.C., Denny W.A., 1999. Structure−Activity Relationships for Substituted Bis(acridine-4-carboxamides): A New Class of Anticancer Agents. J Med Chem. 42(13), 2383-2393.
57. Denny W.A., 2002. Acridine derivatives as chemotherapeutic agents. Curr Med Chem. 9(18), 1655-1665.
58. Akbari S., Soodi M., Hajimehdipoor H., Ataei N., 2019. Protective effects of Sanguisorba minor and Ferulago angulata total extracts against beta-amyloid induced cytotoxicity and oxidative stress in cultured cerebellar granule neurons. Journal of Herbmed Pharmacology. 8(3), 248-255.
59. Ataei N., Soodi M., Hajimehdipoor H., Akbari S., Alimohammadi M., 2020. Cerasus microcarpa and Amygdalus scoparia methanolic extract protect cultured cerebellar granule neurons against β-amyloid-induced toxicity and oxidative stress. Journal of Advances in Medical and Biomedical Research. 28(126), 23-32.
60. Marco-Contelles J., Leon R., de los Rios C., Samadi A., Bartolini M., Andrisano V., Huertas O., Barril X., Luque F.J., Rodriguez-Franco M.I., Lopez B., Lopez M.G., Garcia A.G., Carreiras Mdo C., Villarroya M., 2009. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. J Med Chem. 52(9), 2724-2732.
61. Jafarzadeh E., Shoeibi S., Bahramvand Y., Nasrollahi E., Maghsoudi AS., Yazdi F., KarkonShayan S., Hassani S., 2022. Turmeric for Treatment of Irritable Bowel Syndrome: A Systematic Review of Population-Based Evidence. Iran. J Public Health. 51(6), 1223.
62. Alizadeh A., Moradi M., Irannejad V.S., 2023. Effects of Postbiotics from Food Probiotic and Protective Cultures on Proliferation and Apoptosis in HCT-116 Colorectal Cancer Cells. Appl. Food Biotechnol. 10(2), 85-101.
63. Marco-Contelles J., Leon R., de los Rios C., Samadi A., Bartolini M., Andrisano V., Huertas O., Barril X., Luque FJ., Rodriguez-Franco MI., Lopez B, Lopez MG., Garcia AG., Carreiras Mdo C., Villarroya M., 2009. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease. J Med Chem. 52(9), 2724-2732.
64. Karkon-Shayan S., Aliashrafzadeh H., Dianat-Moghadam H., Rastegar-Pouyani N., Majidi M., Zarei M., Bahramvand Y., Babaniamansour S., Jafarzadeh E.,2023. Resveratrol as an antitumor agent for glioblastoma multiforme: Targeting resistance and promoting apoptotic cell deaths. Acta Histochem. 1;125(6):152058.
65. Munoz-Ruiz P., Rubio L., Garcia-Palomero E., Dorronsoro I., del Monte-Millan M., Valenzuela R., Usan P., de Austria C., Bartolini M., Andrisano V., Bidon-Chanal A., Orozco M., Luque FJ., Medina M., Martinez A., 2005. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. J Med Chem. 48(23), 7223-7233.
