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Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents

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Abstract

Objective

Neuroprotection is a precise target for the treatment of neurodegenerative diseases, ischemic stroke, and traumatic brain injury. Pyrimidine and its derivatives have been proven to use antiviral, anticancer, antioxidant, and antimicrobial activity prompting us to study the neuroprotection and anti-inflammatory activity of the triazole-pyrimidine hybrid on human microglia and neuronal cell model.

Methods

A series of novel triazole-pyrimidine-based compounds were designed, synthesized and characterized by mass spectra, 1HNMR, 13CNMR, and a single X-Ray diffraction analysis. Further, the neuroprotective, anti-neuroinflammatory activity was evaluated by cell viability assay (MTT), Elisa, qRT-PCR, western blotting, and molecular docking.

Results

The molecular results revealed that triazole-pyrimidine hybrid compounds have promising neuroprotective and anti-inflammatory properties. Among the 14 synthesized compounds, ZA3-ZA5, ZB2-ZB6, and intermediate S5 showed significant anti-neuroinflammatory properties through inhibition of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production in LPS-stimulated human microglia cells. From 14 compounds, six (ZA2 to ZA6 and intermediate S5) exhibited promising neuroprotective activity by reduced expression of the endoplasmic reticulum (ER) chaperone, BIP, and apoptosis marker cleaved caspase-3 in human neuronal cells. Also, a molecular docking study showed that lead compounds have favorable interaction with active residues of ATF4 and NF-kB proteins.

Conclusion

The possible mechanism of action was observed through the inhibition of ER stress, apoptosis, and the NF-kB inflammatory pathway. Thus, our study strongly indicates that the novel scaffolds of triazole-pyrimidine-based compounds can potentially be developed as neuroprotective and anti-neuroinflammatory agents.

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Abbreviations

AD:

Alzheimer’s disease

BBB:

Blood-brain barrier

CHCl3 :

Chloroform

DMSO:

Dimethyl sulfoxide

ER:

Endoplasmic reticulum

HMC3:

Human microglia clone 3 cells

LPS:

Lipopolysaccharide

MeOH:

Methanol

Mp:

Melting point

NMR:

Nuclear Magnetic Resonance

OGD/R:

Oxygen-glucose deprivation/Reperfusion

PD:

Parkinson’s disease

ppm:

Parts per million

POCl3 :

Phosphorus oxychloride

K2CO3 :

Potassium carbonate

qRT-PCR:

Quantitative Real-Time Polymerase Chain Reaction

Rt:

Room temperature

THF:

Tetrahydrofuran

TLC:

Thin-layer chromatography

UV:

Ultraviolet

References

  1. Seidl SE, Potashkin JA. The Promise of Neuroprotective Agents in Parkinson’s Disease. Front Neurol. 20112; 68.

  2. Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C. Neuroprotection for Stroke: Current Status and Future Perspectives. Int J Mol Sci. 2012;13:11753–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mattson MP, Magnus T. Ageing and neuronal vulnerability. Nat Rev Neurosci. 2006;7:278–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ning X, Guo Y, Wang X, Ma X, Tian C, Shi X, Zhu R, Cheng C, Du Y, Ma Z, Zhang Z, Liu J. Design, Synthesis, and Biological Evaluation of ( E )-3,4-Dihydroxystyryl Aralkyl Sulfones and Sulfoxides as Novel Multifunctional Neuroprotective Agents. J Med Chem. 2014;57:4302–12.

    Article  CAS  PubMed  Google Scholar 

  5. Rajah GB, Ding Y. Experimental neuroprotection in ischemic stroke: a concise review, Neurosurg Focus. 2017; 42.

  6. Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9:42.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nagesh HN, Naidu KM, Rao DH, Sridevi JP, Sriram D, Yogeeswari P, Chandra Sekhar KVG. Design, synthesis and evaluation of 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues as antimycobacterial agents. Bioorg Med Chem. 2013; Lett. 23 : 6805–6810.

  8. Zhang S, Xu Z, Gao C, Ren Q-C, Chang L, Lv Z-S, Feng L-S. Triazole derivatives and their anti-tubercular activity. Eur J Med Chem. 2017;138:501–13.

    Article  CAS  PubMed  Google Scholar 

  9. Cocco MT, Congiu C, Onnis V, Piras R. Synthesis and antitumor evaluation of 6-thioxo-, 6-oxo- and 2,4-dioxopyrimidine derivatives. Farmaco. 2001;56:741–8.

    Article  CAS  PubMed  Google Scholar 

  10. Ashour HM, Shaaban OG, Rizk OH, El-Ashmawy IM. Synthesis and biological evaluation of thieno [2′,3′:4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines as anti-inflammatory and analgesic agents. Eur J Med Chem. 2013;62:341–51.

    Article  CAS  PubMed  Google Scholar 

  11. Kharb R, Sharma PC, Yar MS. Pharmacological significance of triazole scaffold. J Enzyme Inhib Med Chem. 2011;26:1–21.

    Article  CAS  PubMed  Google Scholar 

  12. Oukoloff K, Lucero B, Francisco KR, Brunden KR, Ballatore C. 1,2,4-Triazolo[1,5-a]pyrimidines in drug design. Eur J Med Chem. 2019;165:332–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Manzoor S, Gabr MT, Rasool B, Pal K, Hoda N. Dual targeting of acetylcholinesterase and tau aggregation: Design, synthesis and evaluation of multifunctional deoxyvasicinone analogues for Alzheimer’s disease. Bioorg Chem. 2021; 105354.

  14. Rani A, Singh G, Singh A, Maqbool U, Kaur G, Singh J. CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review. RSC Adv. 2020;10:5610–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bonandi E, Christodoulou MS, Fumagalli G, Perdicchia D, Rastelli G, Passarella D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov Today. 2017;22:1572–81.

    Article  CAS  PubMed  Google Scholar 

  16. Manzoor S, Petreni A, Raza MK, Supuran CT, Hoda N. Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies. Bioorg Med Chem Lett. 202148: 128249.

  17. Shafi S, Mahboob Alam M, Mulakayala N, Mulakayala C, Vanaja G, Kalle AM, Pallu R, Alam MS. Synthesis of novel 2-mercapto benzothiazole and 1,2,3-triazole based bis-heterocycles: Their anti-inflammatory and anti-nociceptive activities. Eur. J Med Chem 2012; 49:324–333.

  18. Settypalli T, Chunduri VR, Kerru N, Nallapaneni HK, Chintha VR, Daggupati T, Yeguvapalli S, Wudayagiri R. Design, synthesis, neuroprotective and antibacterial activities of 1,2,4-Triazolo[3,4-b]1,3,4-thiadiazole Linked Thieno[2,3-d]pyrimidine derivatives and in silico docking studies. ChemistrySelect. 2019;4:1627–34.

    Article  CAS  Google Scholar 

  19. Holloway PM, Gavins FNE. Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives. Stroke. 2016;47:561–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zipp F, Aktas O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci. 2006;29:518–27.

    Article  CAS  PubMed  Google Scholar 

  21. Wang X-J, Wang M-H, Fu X-T, Hou Y-J, Chen W, Tian D-C, Bai S-Y, Fu X-Y. Selenocysteine antagonizes oxygen glucose deprivation-induced damage to hippocampal neurons. Neural Regen Res. 2018;13:1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. le Feber J, Dummer A, Hassink GC, van Putten MJAM, Hofmeijer J. Evolution of excitation-inhibition ratio in cortical cultures exposed to hypoxia. Front Cell Neurosci. 2018;12:183.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang B, Guo H, Li X, Yue L, Liu H, Zhao L, Bai H, Liu X, Wu X, Qu Y. Adiponectin attenuates oxygen-glucose deprivation-induced mitochondrial oxidative injury and apoptosis in hippocampal HT22 cells via the JAK2/STAT3 pathway. Cell Transplant. 2018;27:1731–43.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Song Y, Du Y, Zou W, Luo Y, Zhang X, Fu J. Involvement of impaired autophagy and mitophagy in Neuro-2a cell damage under hypoxic and/or high-glucose conditions. Sci Rep. 2018;8:3301.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shu K, Zhang Y. Protodioscin protects PC12 cells against oxygen and glucose deprivation-induced injury through miR-124/AKT/Nrf2 pathway. Cell Stress Chaperones. 2019;24:1091–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Haeri M, Knox BE. Endoplasmic reticulum stress and unfolded protein response pathways: potential for treating age-related retinal degeneration. J Ophthalmic Vis Res. 2012;7:45–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kruger TM, Bell KJ, Lansakara TI, Tivanski AV, Doorn JA, Stevens LL. Reduced extracellular matrix stiffness prompts SH-SY5Y cell softening and actin turnover to selectively increase Aβ(1–42) endocytosis. ACS Chem Neurosci. 2019;10:1284–93.

    Article  CAS  PubMed  Google Scholar 

  28. Jantas D, Pytel M, Mozrzymas JW, Leskiewicz M, Regulska M, Antkiewicz-Michaluk L, Lason W. The attenuating effect of memantine on staurosporine-, salsolinol- and doxorubicin-induced apoptosis in human neuroblastoma SH-SY5Y cells. Neurochem Int. 2008;52:864–77.

    Article  CAS  PubMed  Google Scholar 

  29. Heusinkveld HJ, Westerink RHS. Comparison of different in vitro cell models for the assessment of pesticide-induced dopaminergic neurotoxicity. Toxicol Vitr. 2017;45:81–8.

    Article  CAS  Google Scholar 

  30. Shipley MM, Mangold CA, Szpara ML. Differentiation of the SH-SY5Y human neuroblastoma cell line. J Vis Exp. 2016;108:53193.

    Google Scholar 

  31. Liu Y, Eaton ED, Wills TE, McCann SK, Antonic A, Howells DW. Human ischaemic cascade studies using SH-SY5Y cells: a systematic review and meta-analysis. Transl Stroke Res. 2018;9:564–74.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kovalevich J, Langford D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Bio. 2013;9–21.

  33. Xicoy H, Wieringa B, Martens GJM. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener. 2017;12:10.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bin Sayeed MS, Alhadidi Q, Shah ZA. Cofilin signaling in hemin-induced microglial activation and inflammation. J Neuroimmunol. 2017;313:46–55.

    Article  Google Scholar 

  35. Bshara H, Osman R, Mansour S, El-Shamy AE-HA. Chitosan and cyclodextrin in intranasal microemulsion for improved brain buspirone hydrochloride pharmacokinetics in rats. Carbohydr Polym. 2014;99:297–305.

    Article  CAS  PubMed  Google Scholar 

  36. Al-Wahaibi LH, Abu-Melha HM, Ibrahim DA. Synthesis of novel 1,2,4-Triazolyl coumarin derivatives as potential anticancer agents. J Chem. 2018;1–8.

  37. Devender N, Gunjan S, Chhabra S, Singh K, Pasam VR, Shukla SK, Sharma A, Jaiswal S, Singh SK, Kumar Y, Lal J, Trivedi AK, Tripathi R, Tripathi RP. Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents. Eur J Med Chem. 2016;109:187–98.

    Article  CAS  PubMed  Google Scholar 

  38. Jordão AK, Afonso PP, Ferreira VF, de Souza MCBV, Almeida MCB, Beltrame CO, Paiva DP, Wardell SMSV, Wardell JL, Tiekink ERT, Damaso CR, Cunha AC. Antiviral evaluation of N-amino-1,2,3-triazoles against Cantagalo virus replication in cell culture. Eur J Med Chem. 2009;44:3777–83.

    Article  PubMed  Google Scholar 

  39. Kumar B, Dwivedi AR, Sarkar B, Gupta SK, Krishnamurthy S, Mantha AK, Parkash J, Kumar V. 4,6-Diphenylpyrimidine derivatives as dual inhibitors of monoamine oxidase and acetylcholinesterase for the treatment of alzheimer’s disease. ACS Chem Neurosci. 2019;10:252–65.

    Article  CAS  PubMed  Google Scholar 

  40. Horchani M, Hajlaoui A, Harrath AH, Mansour L, Ben Jannet H, Romdhane A. New pyrazolo-triazolo-pyrimidine derivatives as antibacterial agents: Design and synthesis, molecular docking and DFT studies. J Mol Struct. 2020;1199: 127007.

  41. Chong C-M, Ma D, Zhao C, Franklin RJM, Zhou Z-Y, Ai N, Li C, Yu H, Hou T, Sa F, Ming-Yuen Lee S. Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models. Free Radic Biol Med. 2015; 89: 1057–1066.

  42. Li C, Bian Y, Feng Y, Tang F, Wang L, Hoi MPM, Ma D, Zhao C, Lee SMY. Neuroprotective effects of BHDPC, a novel neuroprotectant, on experimental stroke by modulating microglia polarization. ACS Chem Neurosci. 2019;10:2434–49.

    Article  CAS  PubMed  Google Scholar 

  43. Marco-Contelles J, León R, de los Ríos C, Guglietta A, Terencio J, López MG, García AG,  Villarroya M. Novel multipotent tacrine−dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of alzheimer’s disease. J Med Chem 2006:49:7607–7610.

  44. Manzoor S, Prajapati SK, Majumdar S, Raza MK, Gabr MT, Kumar S, Pal K, Rashid H, Kumar S, Krishnamurthy S, Hoda N. Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer’s action: Design, synthesis, crystal structure and in-vitro biological evaluation. Eur J Med Chem. 2021;215:113–224.

    Article  Google Scholar 

  45. Kamei K, Maeda N, Katsuragi-Ogino R, Koyama M, Nakajima M, Tatsuoka T, Ohno T, Inoue T. New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects. Bioorg Med Chem Lett. 2005;15:2990–3.

    Article  CAS  PubMed  Google Scholar 

  46. Kumari MA, Rao CV, Triloknadh S, Harikrishna N, Venkataramaiah C, Rajendra W, Trinath D, Suneetha Y. Synthesis, docking and ADME prediction of novel 1,2,3-triazole-tethered coumarin derivatives as potential neuroprotective agents. Res Chem Intermed. 2018;44:1989–2008.

    Article  CAS  Google Scholar 

  47. Pan S, Yan S, Osako T, Uozumi Y. Batch and continuous-flow huisgen 1,3-dipolar cycloadditions with an amphiphilic resin-supported triazine-based polyethyleneamine dendrimer copper catalyst. ACS Sustain Chem Eng. 2017;5:10722–34.

    Article  CAS  Google Scholar 

  48. Arafa WAA, Nayl AEA. Water as a solvent for Ru-catalyzed click reaction: Highly efficient recyclable catalytic system for triazolocoumarins synthesis. Appl Organomet Chem. 2019;33: e5156.

    Article  Google Scholar 

  49. Jardim G, Lima D, Valença W, Lima D, Cavalcanti B, Pessoa C, Rafique J, Braga A, Jacob C, da Silva Júnior E, da Cruz E. Synthesis of selenium-quinone hybrid compounds with potential antitumor activity via Rh-catalyzed C-H bond activation and click reactions. Molecules. 2017; 23: 83.

  50. Amen OM, Sarker SD, Ghildyal R, Arya A. Endoplasmic reticulum stress activates unfolded protein response signaling and mediates inflammation, obesity, and cardiac dysfunction: therapeutic and molecular approach. Front Pharmacol. 2019;10:977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kohno K, Normington K, Sambrook J, Gething MJ, Mori K. The promoter region of the yeast KAR2 (BiP) gene contains a regulatory domain that responds to the presence of unfolded proteins in the endoplasmic reticulum. Mol Cell Biol. 1993;13:877–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Munro S, Pelham HRB. An hsp70-like protein in the ER: Identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell. 1986;46:291–300.

    Article  CAS  PubMed  Google Scholar 

  53. Tu BP, Weissman JS. Oxidative protein folding in eukaryotes. J Cell Biol. 2004;164:341–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Physiol. 2007;292:353–61.

    Article  Google Scholar 

  55. Walker N, Stuart D. An empirical method for correcting diffractometer data for absorption effects. Acta Crystallogr Sect A Found Crystallogr. 1983;39:158–66.

    Article  Google Scholar 

  56. Sheldrick GM. Crystal structure refinement with SHELXL. Acta Crystallogr Sect C Struct Chem. 2015;71:3–8.

    Article  Google Scholar 

  57. Farrugia LJ. WinGX and ORTEP for Windows : an update. J Appl Crystallogr. 2012;45:849–54.

    Article  CAS  Google Scholar 

  58. Nash KM, Schiefer IT, Shah ZA. Development of a reactive oxygen species-sensitive nitric oxide synthase inhibitor for the treatment of ischemic stroke. Free Radic Biol Med. 2018;115:395–404.

    Article  CAS  PubMed  Google Scholar 

  59. Gil VMS, Oliveira NC. On the use of the method of continuous variations. J Chem Educ. 1990;67:473.

    Article  CAS  Google Scholar 

  60. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Comput Chem. 2009;30:2785–2791.

  61. Abidi M, Khan MS, Ahmad S, Kausar T, Nayeem SM, Islam S, Ali A, Alam K. Moinuddin, Biophysical and biochemical studies on glycoxidatively modified human low density lipoprotein. Arch Biochem Biophys. 2018;645:87–99.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

MSM is highly thankful to the University Grants Commission, Government of India, for financial assistance through Central University. Ph.D. Student’s Fellowship. DAA was supported by a Scholarship from Taif University, Saudi Arabia Cultural Mission. The study was partly supported by Grants from the American Heart Association (17AIREA33700076/Z.A.S./2017) and the National Institute of Neurological Disorders and Stroke, National Institute of Health (R01NS112642) to ZAS.

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Author notes

  1. Shoaib Manzoor and Daniyah A. Almarghalani these authors contributed equally to this work.

Authors and Affiliations

  1. Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia Central University, New Delhi, India, 110025

    Shoaib Manzoor & Nasimul Hoda

  2. Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA

    Daniyah A. Almarghalani, Antonisamy William James & Zahoor A. Shah

  3. Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India

    Md Kausar Raza

  4. Department of Chemistry, Aligarh Muslim University, Aligarh, UP, 202002, India

    Tasneem Kausar & Shahid M. Nayeem

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  1. Shoaib Manzoor
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  3. Antonisamy William James
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Contributions

NH and ZAS were in charge of the research. MSM was involved in the design and synthesis of the compounds under the supervision of NH. SM SM also performed the molecular docking studies and drafting of the manuscript. MKR and MSM analyzed chemical data. DA and AWJ performed in vitro and molecular experiments under the supervision of ZAS, KTK and SMN performed the docking and DMD simulation. SM, DA, and AWJ wrote the manuscript; ZAS corrected the manuscript. All the authors contributed to and approved the final manuscript.

Corresponding authors

Correspondence to Nasimul Hoda or Zahoor A. Shah.

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Manzoor, S., Almarghalani, D.A., James, A.W. et al. Synthesis and Pharmacological Evaluation of Novel Triazole-Pyrimidine Hybrids as Potential Neuroprotective and Anti-neuroinflammatory Agents. Pharm Res 40, 167–185 (2023). https://doi.org/10.1007/s11095-022-03429-1

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