Unveiling of the novel benzothiazole derived thiazolidinone derivatives: in vitro and in silico insights to design a promising agent for anti-Alzheimer’s disease
-
Yousaf Khan
,
Anila Mukhtiar
Abstract
The present investigation explained various heterocyclic moieties particularly the thiazolidinone scaffold (1–16) which were synthesized from benzothiazole as promising anti-Alzheimer agent. In this, we have unveiled the synthetic path for generation of thiazolidinone scaffolds which was initiated benzothiazole having 2-amine moiety. These synthesized scaffolds were then inveterate through several analytical techniques including high-resolution electron impact mass spectrometry (HREI-MS), proton nuclear magnetic resonance (1H NMR), and carbon-13 nuclear magnetic resonance (13C NMR). The anti-Alzheimer potential of these compounds was evaluated through molecular docking studies to examine their interactions with target proteins. Additionally, ADMET analysis was performed to assess drug-likeness and pharmacokinetic properties. Among the synthesized analogs, scaffold-3 emerged as the most promising inhibitor compared to other derivatives in the series. This study highlights the potential of thiazolidinone derivatives in the development of novel anti-Alzheimer drugs and underscores the need for further optimization to enhance their therapeutic efficacy.
Acknowledgments
The authors express their gratitude to Research Supporting Project number (RSP2025R335) King Saud University Riyadh Saudi Arabia.
-
Research ethics: Not applicable.
-
Informed consent: Not applicable.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: None declared.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: None declared.
-
Data availability: Not applicable.
References
1. Nichols, E, Steinmetz, JD, Vollset, SE, Fukutaki, K, Chalek, J, Abd-Allah, F, et al.. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2022;7:105–25. https://doi.org/10.1016/s2468-2667(21)00249-8.Suche in Google Scholar PubMed PubMed Central
2. Watkins, PB, Zimmerman, HJ, Knapp, MJ, Gracon, SI, Lewis, KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994;271:992–8. https://doi.org/10.1001/jama.1994.03510370044030.Suche in Google Scholar
3. Amenta, F, Parnetti, L, Gallai, V, Wallin, A. Treatment of cognitive dysfunction associated with Alzheimer’s disease with cholinergic precursors. Ineffective treatments or inappropriate approaches. Mech Ageing Dev 2001;122:2025–40. https://doi.org/10.1016/s0047-6374(01)00310-4.Suche in Google Scholar PubMed
4. Baqi, A, Samiullah, R, Rehman, W, Bibi, I, Menaa, F, Khan, Y, et al.. Identification and validation of functional miRNAs and their main targets in Sorghum bicolor. Mol Biotechnol 2025;67:123–37. https://doi.org/10.1007/s12033-023-00988-5.Suche in Google Scholar PubMed
5. Baqi, A, Samiullah, Khan, J, Sadiq, A, Khan, Y, Ali, S, et al.. Computational identification and experimental validation of novel Saccharum officinarum microRNAs along with their targets through RT-PCR approach. Plant Signal Behav 2025;20:2452334. https://doi.org/10.1080/15592324.2025.2452334.Samiullah.Suche in Google Scholar
6. Baqi, A, Ullah, S, Ayub, M, Saleem, MZ, Khan, GM. Genome-wide profiling of novel conserved Zea mays microRNAs along with their key biological, molecular and cellular targets and validation using an RT-PCR platform. Karbala Int J Modern Sci 2024;10:4. https://doi.org/10.33640/2405-609x.3336.Suche in Google Scholar
7. Hampel, H, Mesulam, MM, Cuello, AC, Farlow, MR, Giacobini, MR, Grossberg, E, et al.. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018;141:1917–33. https://doi.org/10.1093/brain/awy132.Suche in Google Scholar PubMed PubMed Central
8. Gibbs, D. Dispatches from the land of Alzheimer’s. Cambridge: Cambridge University Press; 2024.10.1017/9781009430067Suche in Google Scholar
9. Braak, H, Thal, DR, Ghebremedhin, E, Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 2011;70:960–9. https://doi.org/10.1097/nen.0b013e318232a379.Suche in Google Scholar
10. Ferreira, JP, Albuquerque, HM, Cardoso, SM, Silva, AM, Silva, VL. Dual-target compounds for Alzheimer’s disease: natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur J Med Chem 2021;221:113492. https://doi.org/10.1016/j.ejmech.2021.113492.Suche in Google Scholar PubMed
11. Bortolami, M, Pandolfi, F, de Vita, D, Carafa, C, Messore, A, Di Santo, R, et al.. New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation. Eur J Med Chem 2020;198:112350. https://doi.org/10.1016/j.ejmech.2020.112350.Suche in Google Scholar PubMed
12. Giacobini, E. Cholinesterases: new roles in brain function and in Alzheimer’s disease. Neurochem Res 2003;28:515. https://doi.org/10.1023/a:1022869222652.10.1023/A:1022869222652Suche in Google Scholar PubMed
13. Holzgrabe, U, Kapková, P, Alptüzün, V, Scheiber, J, Kugelmann, E. Targeting acetylcholinesterase to treat neurodegeneration. Expert Opin Ther Targets 2007;11:161. https://doi.org/10.1517/14728222.11.2.161.Suche in Google Scholar PubMed
14. Mushtaq, G, Greig, NH, Khan, JA, Kamal, MA. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 2014;13:1432–9. https://doi.org/10.2174/1871527313666141023141545.Suche in Google Scholar PubMed PubMed Central
15. Rahim, F, Ullah, H, Taha, M, Wadood, A, Javed, MT, Rehman, W, et al.. Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide-based Schiff bases. Bioorg Chem 2016;68:30–40. https://doi.org/10.1016/j.bioorg.2016.07.005.Suche in Google Scholar PubMed
16. Wang, J, Timchalk, C, Lin, Y. Carbon nanotube-based electrochemical sensor for assay of salivary cholinesterase enzyme activity: an exposure biomarker of organophosphate pesticides and nerve agents. Environ Sci Technol 2008;42:2688. https://doi.org/10.1021/es702335y.Suche in Google Scholar PubMed
17. Kalantarian, SJ, Kefayati, H, Montazeri, N. Synthesis and antimicrobial evaluation of novel tris-thiadiazole derivatives. J Heterocycl Chem 2022;59:1253–9. https://doi.org/10.1002/jhet.4466.Suche in Google Scholar
18. Revi, M. Alzheimer’s disease therapeutic approaches. In: GeNeDis 2018: genetics and neurodegeneration. Cham: Springer; 2020:105–16 pp.10.1007/978-3-030-32633-3_15Suche in Google Scholar PubMed
19. Khan, Y, Rehman, W, Hussain, R, Khan, S, Maalik, A. Benzothiazole-based 1, 3, 4-thiadiazole hybrids derivatives as effective inhibitors of urease and thymidine phosphorylase: synthesis, in vitro and in silico approaches. J Mol Struct 2023;1291:135945. https://doi.org/10.1016/j.molstruc.2023.135945.Suche in Google Scholar
20. Khan, S, Iqbal, S, Taha, M, Hussain, R, Rahim, F, Shah, M, et al.. Synthesis, in vitro biological assessment, and molecular docking study of benzimidazole-based thiadiazole derivatives as dual inhibitors of α-amylase and α-glucosidase. Front Chem 2023;11:1125915. https://doi.org/10.3389/fchem.2023.1125915.Suche in Google Scholar PubMed PubMed Central
21. Khan, S, Iqbal, S, Taha, M, Rahim, F, Shah, M, Ullah, H, et al.. Synthesis, in vitro biological evaluation and in silico molecular docking studies of indole based thiadiazole derivatives as dual inhibitor of acetylcholinesterase and butyrylchloinesterase. Molecules 2022;21:368. https://doi.org/10.3390/molecules27217368.Suche in Google Scholar PubMed PubMed Central
22. Rostom, SA, El-Ashmawy, IM, AbdElRazik, HA, Badr, MH, Ashour, HM. Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents. Bioorg Med Chem 2009;17:882–95. https://doi.org/10.1016/j.bmc.2008.11.035.Suche in Google Scholar PubMed
23. Britschgi, M, Greyerz, S, Burkhart, C, Pichler, W. Molecular aspects of drug recognition by specific T cells. Curr Drug Targets 2003;4:1–11. https://doi.org/10.2174/1389450033347082.Suche in Google Scholar PubMed
24. Luzina, EL, Popov, AV. Synthesis and anticancer activity of N-bis (trifluoromethyl) alkyl-N′-thiazolyl and N-bis (trifluoromethyl) alkyl-N′-benzothiazolylureas. Eur J Med Chem 2009;44:4944–53. https://doi.org/10.1016/j.ejmech.2009.08.007.Suche in Google Scholar PubMed
25. Turan-Zitouni, G, Chevallet, P, Kilic, FS, Erol, K. Synthesis of some thiazolyl-pyrazoline derivatives and preliminary investigation of their hypotensive activity. Eur J Med Chem 2000;35:635–41. https://doi.org/10.1016/s0223-5234(00)00152-5.Suche in Google Scholar PubMed
26. Khan, Y, Khan, S, Hussain, R, Rehman, W, Maalik, A, Gulshan, U, et al.. Identification of indazole-based thiadiazole-bearing thiazolidinone hybrid derivatives: theoretical and computational approaches to develop promising anti-Alzheimer’s candidates. Pharmaceuticals 2023;16:1667. https://doi.org/10.3390/ph16121667.Suche in Google Scholar PubMed PubMed Central
27. Karaca, Ş, Osmaniye, D, Sağlık, BN, Levent, S, Ilgın, S, Özkay, Y, et al.. Synthesis of novel benzothiazole derivatives and investigation of their enzyme inhibitory effects against Alzheimer’s disease. RSC Adv 2022;12:23626–36. https://doi.org/10.1039/d2ra03803j.Suche in Google Scholar PubMed PubMed Central
28. Ellman, GL, Courtney, KD, Andres, JV, Featherstone, RM. A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem Pharmacol 1961;7:88–95. https://doi.org/10.1016/0006-2952(61)90145-9.Suche in Google Scholar PubMed
29. Khan, S, Iqbal, S, Rehman, W, Hussain, N, Hussain, R, Ali, F, et al.. Synthesis, Molecular docking and ADMET studies of bis-benzimidazole-based thiadiazole derivatives as potent inhibitors, in vitro α-amylase and α-glucosidase. Arab J Chem 2023;16:104847. https://doi.org/10.1016/j.arabjc.2023.104847.Suche in Google Scholar
30. Khan, Y, Rehman, W, Hussain, R, Khan, S, Maalik, A. Benzothiazole-based 1, 3, 4-thiadiazole hybrids derivatives as effective inhibitors of urease and thymidine phosphorylase: synthesis, in vitro and in silico approaches. J Mol Struct 2023;1291:135945. https://doi.org/10.1016/j.molstruc.2023.135945.Suche in Google Scholar
31. Khan, S, Ullah, H, Hussain, R, Khan, Y, Khan, MU, Khan, M, et al.. Synthesis, in vitro bio-evaluation, and molecular docking study of thiosemicarbazone-based isatin/bis-schiff base hybrid analogues as effective cholinesterase inhibitors. J Mol Struct 2023;1284:135351. https://doi.org/10.1016/j.molstruc.2023.135351.Suche in Google Scholar
32. Khan, S, Rehman, W, Rahim, F, Hussain, R, Obaidullah, AJ, Alotaibi, HF, et al.. Bis-indole based triazine derivatives: synthesis, characterization, in vitro β-Glucuronidase anti-cancer and anti-bacterial evaluation along with in silico molecular docking and ADME analysis. Arab J Chem 2023;16:104970. https://doi.org/10.1016/j.arabjc.2023.104970.Suche in Google Scholar
33. Khan, S, Iqbal, S, Khan, M, Rehman, W, Shah, M, Hussain, R, et al.. Design, synthesis, in silico testing, and in vitro evaluation of thiazolidinone-based benzothiazole derivatives as inhibitors of α-amylase and α-glucosidase. Pharmaceuticals 2022;15:1164. https://doi.org/10.3390/ph15101164.Suche in Google Scholar PubMed PubMed Central
34. Hussain, R, Rehman, W, Rahim, F, Khan, S, Alanazi, AS, Alanazi, MM, et al.. Synthesis, in vitro thymidine phosphorylase inhibitory activity and molecular docking study of novel pyridine-derived bis-oxadiazole bearing bis-schiff base derivatives. Arab J Chem 2023;16:104773. https://doi.org/10.1016/j.arabjc.2023.104773.Suche in Google Scholar
35. Khan, Y, Rehman, W, Hussain, R, Khan, S, Malik, A, Khan, M, et al.. New biologically potent benzimidazole‐based‐triazole derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors along with molecular docking study. J Heterocycl Chem 2022;59:2225–39. https://doi.org/10.1002/jhet.4553.Suche in Google Scholar
36. Hussain, R, Rehman, W, Rahim, F, Khan, S, Taha, M, Khan, Y, et al.. Discovery of imidazopyridine derived oxadiazole-based thiourea derivatives as potential anti-diabetic agents: synthesis, in vitro antioxidant screening and in silico molecular modeling approaches. J Mol Struct 2023;1293:136185. https://doi.org/10.1016/j.molstruc.2023.136185.Suche in Google Scholar
37. Hussain, R, Khan, S, Ullah, H, Ali, F, Khan, Y, Sardar, A, et al.. Benzimidazole-based schiff base hybrid scaffolds: a promising approach to develop multi-target drugs for Alzheimer’s disease. Pharmaceuticals 2023;16:1278. https://doi.org/10.3390/ph16091278.Suche in Google Scholar PubMed PubMed Central
38. Hussain, R, Rehman, W, Khan, S, Maalik, A, Hefnawy, W, Alanazi, AS, et al.. Imidazopyridine-based thiazole derivatives as potential antidiabetic agents: synthesis, in vitro bioactivity, and in silico molecular modeling approach. Pharmaceuticals 2023;16:1288. https://doi.org/10.3390/ph16091288.Suche in Google Scholar PubMed PubMed Central
Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/znc-2024-0244).
© 2025 Walter de Gruyter GmbH, Berlin/Boston
