SpringerLink
Log in

Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitor for the Treatment of Alzheimer’s Disease

  • Research
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Brazil)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Data Availability

All data generated or analyzed during this study are included in this article. There are no separate or additional files.

Abbreviations

AchE:

Acetylcholinestrase

AD:

Alzheimer’s disease

Aβ:

Amyloid-beta

Bax:

Bcl-2-associated X protein

DON:

Donepezil

ELT:

Escape latency time

GSH:

Reduced glutathione

LDH:

Lactate dehydrogenase

MAP:

Myelin associated proteins

MBP:

Myelin basic protein

MD:

Malondialdehyde

MEM:

Memantine

NEFL:

Neurofilament light chain

NMDA:

N-Methyl-d aspartate

No:

Nitric oxide

SOD:

Superoxide dismutase

SSZ:

6-chloro-N-cyclohexyl-4-(1Hpyrollo[2,3-b] pyridin-3-yl] pyridin-2-amine

TSTQ:

Time spent in the target quadrant

LA:

Locomotor activity

MWM:

Morris water maze

BCT:

Beam-crossing task

References

  1. Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, Kirabali T, Krolak-Salmon P et al (2023) Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement 19(2):658–670. https://doi.org/10.1002/alz.12694

  2. Li X, Feng X, Sun X, Hou N, Han F, Liu Y (2022) Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2019. Front Aging Neurosci 14. https://doi.org/10.3389/fnagi.2022.937486

  3. Jabir NR, Khan FR, Tabrez S (2018) Cholinesterase targeting by polyphenols: a therapeutic approach for the treatment of Alzheimer’s disease. CNS Neurosci Ther 24(9):753–762. https://doi.org/10.1111/cns.12971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hoque M, Samanta A, Alam SSM, Zughaibi TA, Kamal MA, Tabrez S (2023) Nanomedicine-based immunotherapy for Alzheimer’s disease. Neurosci Biobehav Rev 144:104973. https://doi.org/10.1016/j.neubiorev.2022.104973

    Article  CAS  PubMed  Google Scholar 

  5. Makhaeva GF, Lushchekina SV, Kovaleva NV, Yu Astakhova T, Boltneva NP, Rudakova EV, Serebryakova OG, Proshin AN et al (2021) Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer’s disease treatment. Bioorg Chem 112:104974. https://doi.org/10.1016/j.bioorg.2021.104974

    Article  CAS  PubMed  Google Scholar 

  6. Islam BU, Jabir NR, Tabrez S (2019) The role of mitochondrial defects and oxidative stress in Alzheimer’s disease. J Drug Target 27(9):932–942. https://doi.org/10.1080/1061186X.2019.1584808

    Article  CAS  PubMed  Google Scholar 

  7. Rai SN, Singh C, Singh A, Singh MP, Singh BK (2020) Mitochondrial dysfunction: a potential therapeutic target to treat Alzheimer’s disease. Mol Neurobiol 57(7):3075–3088. https://doi.org/10.1007/s12035-020-01945-y

    Article  CAS  PubMed  Google Scholar 

  8. Rai SN, Zahra W, Birla H, Singh SS, Singh SP (2018) Mild endoplasmic reticulum stress ameliorates lpopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. Front Aging Neurosci 10:192. https://doi.org/10.3389/fnagi.2018.00192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tripathi PN, Srivastava P, Sharma P, Tripathi MK, Seth A, Tripathi A, Rai SN, Singh SP et al (2019) Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory. Bioorg Chem 85:82–96. https://doi.org/10.1016/j.bioorg.2018.12.017

  10. Singh M, Kaur M, Vyas B, Silakari O (2018) Design, synthesis and biological evaluation of 2-Phenyl-4H-chromen-4-one derivatives as polyfunctional compounds against Alzheimer’s disease. Med Chem Res 27(2):520–530. https://doi.org/10.1007/s00044-017-2078-4

    Article  CAS  Google Scholar 

  11. Srivastava P, Tripathi PN, Sharma P, Rai SN, Singh SP, Srivastava RK, Shankar S, Shrivastava SK (2019) Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Eur J Med Chem 163:116–135. https://doi.org/10.1016/j.ejmech.2018.11.049

    Article  CAS  PubMed  Google Scholar 

  12. Zhang N, Gan L, **ang G, Xu J, Jiang T, Li Y, Wu Y, Ni R et al (2024) Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a real-world pharmacovigilance study. Front Pharmacol 14. https://doi.org/10.3389/fphar.2023.1343650

  13. Obrenovich M, Tabrez S, Siddiqui B, McCloskey B, Perry G (2020) The microbiota-gut-brain axis-heart shunt part II: prosaic foods and the brain-heart connection in Alzheimer disease. Microorganisms 8(4):493. https://doi.org/10.3390/microorganisms8040493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Long J, Qin F, Luo J, Zhong G, Huang S, **g L, Yi T, Liu J et al (2024) Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg Chem 143:107026. https://doi.org/10.1016/j.bioorg.2023.107026

  15. Drakontaeidi A, Pontiki E (2024) Multi-target-directed cinnamic acid hybrids targeting Alzheimer’s disease. Int J Mol Sci 25(1):582. https://doi.org/10.3390/ijms25010582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hafez DE, Dubiel M, La Spada G, Catto M, Reiner-Link D, Syu Y-T, Abdel-Halim M, Hwang T-L et al (2023) Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease. J Enzyme Inhib Med Chem 38(1):2175821. https://doi.org/10.1080/14756366.2023.2175821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jabir NR, Rehman MT, AlAjmi MF, Ahmed BA, Tabrez S (2023) Prioritization of bioactive compounds envisaging yohimbine as a multi targeted anticancer agent: insight from molecular docking and molecular dynamics simulation. J Biomol Struct Dyn 41(20):10463–10477. https://doi.org/10.1080/07391102.2022.2158137

    Article  CAS  PubMed  Google Scholar 

  18. Jabir NR, Rehman MT, Alsolami K, Shakil S, Zughaibi TA, Alserihi RF, Khan MS, AlAjmi MF et al (2021) Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer’s treatment. Ann Med 53(1):2332–2344. https://doi.org/10.1080/07853890.2021.2009124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jabir NR, Rehman MT, Tabrez S, Alserihi RF, AlAjmi MF, Khan MS, Husain FM, Ahmed BA (2021) Identification of butyrylcholinesterase and monoamine oxidase B targeted ligands and their putative application in Alzheimer’s treatment: a computational strategy. Curr Pharm Des 27(20):2425–2434. https://doi.org/10.2174/1381612827666210226123240

    Article  CAS  PubMed  Google Scholar 

  20. Jabir NR, Shakil S, Tabrez S, Khan MS, Rehman MT, Ahmed BA (2021) In silico screening of glycogen synthase kinase-3β targeted ligands against acetylcholinesterase and its probable relevance to Alzheimer’s disease. J Biomol Struct Dyn 39(14):5083–5092. https://doi.org/10.1080/07391102.2020.1784796

    Article  CAS  PubMed  Google Scholar 

  21. Haghighijoo Z, Akrami S, Saeedi M, Zonouzi A, Iraji A, Larijani B, Fakherzadeh H, Sharifi F et al (2020) N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer’s disease. Bioorg Chem 103:104146. https://doi.org/10.1016/j.bioorg.2020.104146

    Article  CAS  PubMed  Google Scholar 

  22. Konecny J, Misiachna A, Hrabinova M, Pulkrabkova L, Benkova M, Prchal L, Kucera T, Kobrlova T et al (2020) Pursuing the complexity of Alzheimer’s disease: discovery of fluoren-9-amines as selective butyrylcholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Biomolecules 11(1):3. https://doi.org/10.3390/biom11010003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dorababu A (2022) Promising heterocycle-based scaffolds in recent (2019–2021) anti-Alzheimer’s drug design and discovery. Eur J Pharmacol 920:174847. https://doi.org/10.1016/j.ejphar.2022.174847

    Article  CAS  PubMed  Google Scholar 

  24. Wójcicka A, Redzicka A (2021) An overview of the biological activity of pyrrolo[3,4-c]pyridine derivatives. Pharmaceuticals (Basel) 14(4):354. https://doi.org/10.3390/ph14040354

    Article  CAS  PubMed  Google Scholar 

  25. Jeelan Basha N, Basavarajaiah SM, Shyamsunder K (2022) Therapeutic potential of pyrrole and pyrrolidine analogs: an update. Mol Divers 26(5):2915–2937. https://doi.org/10.1007/s11030-022-10387-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Istanbullu H, Bayraktar G, Saylam M, Istanbullu H, Bayraktar G, Saylam M (2022) Fused pyridine derivatives: synthesis and biological activities. In: Exploring chemistry with pyridine derivatives. IntechOpen. https://doi.org/10.5772/intechopen.107537

  27. Bianco MdCAD, Marinho DILF, Hoelz LVB, Bastos MM, Boechat N (2021) Pyrroles as privileged scaffolds in the search for new potential HIV inhibitors. Pharmaceuticals (Basel) 14(9):893. https://doi.org/10.3390/ph14090893

    Article  CAS  PubMed  Google Scholar 

  28. Saigal GYSA, Uddin A, Khan S, Abid M, Khan MM (2021) Synthesis, biological evaluation and docking studies of functionalized pyrrolo[3,4-b]pyridine derivatives. ChemistrySelect 6(9):2323–2334. https://doi.org/10.1002/slct.202004781

    Article  CAS  Google Scholar 

  29. Vadukoot AK, Sharma S, Aretz CD, Kumar S, Gautam N, Alnouti Y, Aldrich AL, Heim CE et al (2020) Synthesis and SAR studies of 1H-pyrrolo[2,3-b]pyridine-2-carboxamides as phosphodiesterase 4B (PDE4B) inhibitors. ACS Med Chem Lett 11(10):1848–1854. https://doi.org/10.1021/acsmedchemlett.9b00369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tzvetkov NT, Stammler H-G, Hristova S, Atanasov AG, Antonov L (2019) (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons. Eur J Med Chem 162:793–809. https://doi.org/10.1016/j.ejmech.2018.11.009

    Article  CAS  PubMed  Google Scholar 

  31. Tong Y, Stewart KD, Florjancic AS, Harlan JE, Merta PJ, Przytulinska M, Soni N, Swinger KK et al (2013) Azaindole-based inhibitors of Cdc7 kinase: impact of the Pre-DFG residue, Val 195. ACS Med Chem Lett 4(2):211–215. https://doi.org/10.1021/ml300348c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guzmán-Ruiz MA, Herrera-González A, Jiménez A, Candelas-Juárez A, Quiroga-Lozano C, Castillo-Díaz C, Orta-Salazar E, Organista-Juárez D et al (2021) Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1-42 rat model. BMC Neurosci 22(1):14. https://doi.org/10.1186/s12868-021-00620-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharma S, Verma S, Kapoor M, Saini A, Nehru B (2016) Alzheimer’s disease like pathology induced six weeks after aggregated amyloid-beta injection in rats: increased oxidative stress and impaired long-term memory with anxiety-like behavior. Neurol Res 38(9):838–850. https://doi.org/10.1080/01616412.2016.1209337

    Article  CAS  PubMed  Google Scholar 

  34. Cetin F, Yazihan N, Dincer S, Akbulut G (2013) The effect of intracerebroventricular injection of beta amyloid peptide (1–42) on caspase-3 activity, lipid peroxidation, nitric oxide and NOS expression in young adult and aged rat brain. Turk Neurosurg 23(2):144–150. https://doi.org/10.5137/1019-5149.JTN.5855-12.1

    Article  PubMed  Google Scholar 

  35. Guo J, Wang Z, Liu R, Huang Y, Zhang N, Zhang R (2020) Memantine, donepezil, or combination therapy-what is the best therapy for Alzheimer’s disease? A network meta-analysis Brain Behav 10(11):e01831. https://doi.org/10.1002/brb3.1831

    Article  PubMed  Google Scholar 

  36. Anoush M, Bijani S, Moslemifar F, Jahanpour F, Kalantari-Hesari A, Hosseini M-J (2023) Edaravone improves streptozotocin-induced memory impairment via alleviation of behavioral dysfunction, oxidative stress, inflammation, and histopathological parameters. Behav Neurol 2023:e9652513. https://doi.org/10.1155/2023/9652513

    Article  Google Scholar 

  37. Zhang Y, Chen H, Li R, Sterling K, Song W (2023) Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther 8(1):248. https://doi.org/10.1038/s41392-023-01484-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chhabra S, Mehan S, Khan Z, Gupta GD, Narula AS (2023) Matrine mediated neuroprotective potential in experimental multiple sclerosis: evidence from CSF, blood markers, brain samples and in-silico investigations. J Neuroimmunol 384. https://doi.org/10.1016/j.jneuroim.2023.578200

  39. Kumar A, Lana E, Kumar R, Lithner CU, Darreh-Shori T (2018) P1–241: soluble amyloid-beta activates choline acetyltransferase. Alzheimer's & Dementia 14 (7S_Part_7):P371-P371. https://doi.org/10.1016/j.jalz.2018.06.246

  40. Alkandari AF, Madhyastha S, Rao MS (2023) N-Acetylcysteine amide against Aβ-induced Alzheimer’s-like pathology in rats. Int J Mol Sci 24(16):12733. https://doi.org/10.3390/ijms241612733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sethi P, Mehan S, Khan Z, Chhabra S (2023) Acetyl-11-keto-beta boswellic acid(AKBA) modulates CSTC-pathway by activating SIRT-1/Nrf2-HO-1 signalling in experimental rat model of obsessive-compulsive disorder: evidenced by CSF, blood plasma and histopathological alterations. Neurotoxicology 98:61–85. https://doi.org/10.1016/j.neuro.2023.08.001

    Article  CAS  PubMed  Google Scholar 

  42. Alharbi M, Alshammari A, Kaur G, Kalra S, Mehan S, Suri M, Chhabra S, Kumar N et al (2022) Effect of natural adenylcyclase/cAMP/CREB signalling activator forskolin against intra-striatal 6-OHDA-lesioned Parkinson’s rats: preventing mitochondrial, motor and histopathological defects. Molecules 27(22):7951. https://doi.org/10.3390/molecules27227951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Khera R, Mehan S, Bhalla S, Kumar S, Alshammari A, Alharbi M, Sadhu SS (2022) Guggulsterone mediated JAK/STAT and PPAR-gamma modulation prevents neurobehavioral and neurochemical abnormalities in propionic acid-induced experimental model of autism. Molecules (Basel, Switzerland) 27(3):889. https://doi.org/10.3390/molecules27030889

    Article  CAS  PubMed  Google Scholar 

  44. Singh A, Upadhayay S, Mehan S (2021) Inhibition of c-JNK/p38MAPK signaling pathway by Apigenin prevents neurobehavioral and neurochemical defects in ethidium bromide-induced experimental model of multiple sclerosis in rats: evidence from CSF, blood plasma and brain samples. Phytomed Plus 1(4):100139. https://doi.org/10.1016/j.phyplu.2021.100139

    Article  Google Scholar 

  45. Duggal P, Jadaun KS, Siqqiqui EM, Mehan S (2020) Investigation of low dose cabazitaxel potential as microtubule stabilizer in experimental model of Alzheimer’s disease: restoring neuronal cytoskeleton. Curr Alzheimer Res 17(7):601–615. https://doi.org/10.2174/1567205017666201007120112

    Article  CAS  PubMed  Google Scholar 

  46. Bhalla S, Mehan S (2022) 4-Hydroxyisoleucine mediated IGF-1/GLP-1 signalling activation prevents propionic acid-induced autism-like behavioural phenotypes and neurochemical defects in experimental rats. Neuropeptides 96:102296. https://doi.org/10.1016/j.npep.2022.102296

    Article  CAS  PubMed  Google Scholar 

  47. Sharma A, Bhalla S, Mehan S (2022) PI3K/AKT/mTOR signalling inhibitor chrysophanol ameliorates neurobehavioural and neurochemical defects in propionic acid-induced experimental model of autism in adult rats. Metab Brain Dis 37(6):1909–1929. https://doi.org/10.1007/s11011-022-01026-0

    Article  CAS  PubMed  Google Scholar 

  48. Mehan S, Meena H, Sharma D, Sankhla R (2011) JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer’s and various neurodegenerative abnormalities. J Mol Neurosci 43(3):376–390. https://doi.org/10.1007/s12031-010-9454-6

    Article  CAS  PubMed  Google Scholar 

  49. Upadhayay S, Mehan S, Prajapati A, Sethi P, Suri M, Zawawi A, Almashjary MN, Tabrez S (2022) Nrf2/HO-1 signaling stimulation through acetyl-11-keto-beta-boswellic acid (AKBA) provides neuroprotection in ethidium bromide-induced experimental model of multiple sclerosis. Genes (Basel) 13(8):1324. https://doi.org/10.3390/genes13081324

    Article  CAS  PubMed  Google Scholar 

  50. Gupta R, Mehan S, Sethi P, Prajapati A, Alshammari A, Alharbi M, Al-Mazroua HA, Narula AS (2022) Smo-Shh agonist purmorphamine prevents neurobehavioral and neurochemical defects in 8-OH-DPAT-induced experimental model of obsessive-compulsive disorder. Brain Sci 12(3):342. https://doi.org/10.3390/brainsci12030342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rahi S, Gupta R, Sharma A, Mehan S (2021) Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism. Hum Exp Toxicol 40(11):1880–1898. https://doi.org/10.1177/09603271211013456

    Article  CAS  PubMed  Google Scholar 

  52. Prajapati A, Mehan S, Khan Z, Chhabra S, Das Gupta G (2023) Purmorphamine, a Smo-Shh/Gli activator, promotes sonic hedgehog-mediated neurogenesis and restores behavioural and neurochemical deficits in experimental model of multiple sclerosis. Neurochem Res. https://doi.org/10.1007/s11064-023-04082-9

    Article  PubMed  Google Scholar 

  53. Shandilya A, Mehan S, Kumar S, Sethi P, Narula AS, Alshammari A, Alharbi M, Alasmari AF (2022) Activation of IGF-1/GLP-1 Signalling via 4-hydroxyisoleucine prevents motor neuron impairments in experimental ALS-rats exposed to methylmercury-induced neurotoxicity. Molecules (Basel, Switzerland) 27(12):3878. https://doi.org/10.3390/molecules27123878

    Article  CAS  PubMed  Google Scholar 

  54. Sharma S, Mehan S, Khan Z, Gupta GD, Narula AS (2024) Icariin prevents methylmercury-induced experimental neurotoxicity: evidence from cerebrospinal fluid, blood plasma, brain samples, and in-silico investigations. Heliyon 10(1):e24050. https://doi.org/10.1016/j.heliyon.2024.e24050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rajkhowa B, Mehan S, Sethi P, Prajapati A, Suri M, Kumar S, Bhalla S, Narula AS et al (2022) Activating SIRT-1 signalling with the mitochondrial-CoQ10 activator solanesol improves neurobehavioral and neurochemical defects in ouabain-induced experimental model of bipolar disorder. Pharmaceuticals (Basel, Switzerland) 15(8):959. https://doi.org/10.3390/ph15080959

    Article  CAS  PubMed  Google Scholar 

  56. Kumar S, Mehan S, Khan Z, Das Gupta G, Narula AS (2024) Guggulsterone selectively modulates STAT-3, mTOR, and PPAR-gamma signaling in a methylmercury-exposed experimental neurotoxicity: evidence from CSF, blood plasma, and brain samples. Mol Neurobiol. https://doi.org/10.1007/s12035-023-03902-x

    Article  PubMed  Google Scholar 

  57. Kumar N, Sharma N, Khera R, Gupta R, Mehan S (2021) Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain. Metab Brain Dis 36(5):911–925. https://doi.org/10.1007/s11011-021-00691-x

    Article  CAS  PubMed  Google Scholar 

  58. Maramai S, Benchekroun M, Gabr MT, Yahiaoui S (2020) Multitarget therapeutic strategies for Alzheimer’s disease: review on emerging target combinations. Biomed Res Int 2020:5120230. https://doi.org/10.1155/2020/5120230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hughes JD, Blagg J, Price DA, Bailey S, Decrescenzo GA, Devraj RV, Ellsworth E, Fobian YM et al (2008) Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett 18(17):4872–4875. https://doi.org/10.1016/j.bmcl.2008.07.071

    Article  CAS  PubMed  Google Scholar 

  60. Banks WA (2016) From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov 15(4):275–292. https://doi.org/10.1038/nrd.2015.21

    Article  CAS  PubMed  Google Scholar 

  61. Lehmann S, Dumurgier J, Ayrignac X, Marelli C, Alcolea D, Ormaechea JF, Thouvenot E, Delaby C et al (2020) Cerebrospinal fluid A beta 1–40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals. Alzheimers Res Ther 12(1):123. https://doi.org/10.1186/s13195-020-00696-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yoon S-S, AhnJo S-M (2012) Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol Ther 20(3):245–255. https://doi.org/10.4062/biomolther.2012.20.3.245

    Article  CAS  Google Scholar 

  63. Serra-Añó P, Pedrero-Sánchez JF, Hurtado-Abellán J, Inglés M, Espí-López GV, López-Pascual J (2019) Mobility assessment in people with Alzheimer disease using smartphone sensors. J Neuroeng Rehabil 16(1):103. https://doi.org/10.1186/s12984-019-0576-y

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hebert LE, Bienias JL, McCann JJ, Scherr PA, Wilson RS, Evans DA (2010) Upper and lower extremity motor performance and functional impairment in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 25(5):425–431. https://doi.org/10.1177/1533317510367636

    Article  PubMed  PubMed Central  Google Scholar 

  65. Jadhav R, Kulkarni YA (2023) The combination of baicalein and memantine reduces oxidative stress and protects against β-amyloid-induced Alzheimer’s disease in rat model. Antioxidants 12(3):707. https://doi.org/10.3390/antiox12030707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. ** X, Liu M-Y, Zhang D-F, Zhong X, Du K, Qian P, Yao W-F, Gao H et al (2019) Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF-κB signaling pathway. CNS Neurosci Ther 25(5):575–590. https://doi.org/10.1111/cns.13086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Arendash GW, King DL, Gordon MN, Morgan D, Hatcher JM, Hope CE, Diamond DM (2001) Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res 891(1–2):42–53. https://doi.org/10.1016/s0006-8993(00)03186-3

    Article  CAS  PubMed  Google Scholar 

  68. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D et al (2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388(1):9–21. https://doi.org/10.1056/NEJMoa2212948

    Article  PubMed  Google Scholar 

  69. Dhamodharan J, Sekhar G, Muthuraman A (2022) Epidermal growth factor receptor kinase inhibitor ameliorates β-amyloid oligomer-induced alzheimer disease in Swiss albino mice. Molecules 27(16):5182. https://doi.org/10.3390/molecules27165182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Knopp RC, Baumann KK, Wilson ML, Banks WA, Erickson MA (2022) Amyloid beta pathology exacerbates weight loss and brain cytokine responses following low-dose lipopolysaccharide in aged female Tg2576 mice. Int J Mol Sci 23(4):2377. https://doi.org/10.3390/ijms23042377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800. https://doi.org/10.1212/WNL.58.12.1791

    Article  PubMed  Google Scholar 

  72. Shen W-X, Chen J-H, Lu J-H, Peng Y-P, Qiu Y-H (2014) TGF-β1 protection against Aβ1–42-induced neuroinflammation and neurodegeneration in rats. Int J Mol Sci 15(12):22092–22108. https://doi.org/10.3390/ijms151222092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jadaun KS, Sharma A, Siddiqui EM, Mehan S (2022) Targeting abnormal PI3K/AKT/mTOR signaling in intracerebral hemorrhage: a systematic review on potential drug targets and influences of signaling modulators on other neurological disorders. Curr Rev Clin Exp Pharmacol 17(3):174–191. https://doi.org/10.2174/1574884716666210726110021

    Article  CAS  PubMed  Google Scholar 

  74. Minj E, Upadhayay S, Mehan S (2021) Nrf2/HO-1 signaling activator acetyl-11-keto-beta boswellic acid (AKBA)-mediated neuroprotection in methyl mercury-induced experimental model of ALS. Neurochem Res 46(11):2867–2884. https://doi.org/10.1007/s11064-021-03366-2

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.S.K. acknowledges the generous support from the Research Supporting Project (RSP2024R352) by the King Saud University, Riyadh, Kingdom of Saudi Arabia.

Funding

Research Supporting Project (RSP2024R352), King Saud University, Riyadh, Kingdom of Saudi Arabia.

Author information

Author notes

  1. The authors Mohd Shahnawaz Khan and Zuber Khan contributed equally.

Authors and Affiliations

  1. Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia

    Mohd Shahnawaz Khan

  2. Department of Pharmacology, ISF College of Pharmacy (An Autonomous College), Moga, 142001, Punjab, India

    Zuber Khan & Sidharth Mehan

  3. Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, India

    Nasimudeen R. Jabir

  4. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Mohd Suhail, Torki A. Zughaibi & Shams Tabrez

  5. Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Mohd Suhail, Torki A. Zughaibi & Shams Tabrez

  6. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia

    Syed Kashif Zaidi

  7. Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India

    Mohammad Abid

Authors
  1. Mohd Shahnawaz Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zuber Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nasimudeen R. Jabir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sidharth Mehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohd Suhail
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Syed Kashif Zaidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Torki A. Zughaibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammad Abid
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shams Tabrez
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Investigation, methodology, resources, writing first draft, Z.K.; M.S,; N.R.J.; T.A.Z.; formal analysis, data curation, validation, editing, S.M,; S.T,; M.A,; M.K.Z,; M.S.K. All authors agree to be accountable for all aspects of this work, ensuring integrity and accuracy. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Sidharth Mehan, Mohammad Abid or Shams Tabrez.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent to Publish

All authors have given their consent to publish this article.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 287 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khan, M.S., Khan, Z., Jabir, N.R. et al. Synthesis and Neurobehavioral Evaluation of a Potent Multitargeted Inhibitor for the Treatment of Alzheimer’s Disease. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04351-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04351-w

Keywords

Search

Navigation