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Review
. 2023 Nov 14;8(47):44437-44457.
doi: 10.1021/acsomega.3c04960. eCollection 2023 Nov 28.

"Click Chemistry": An Emerging Tool for Developing a New Class of Structural Motifs against Various Neurodegenerative Disorders

Amritha Manoharan  1 , Jayalakshmi Jayan  1 , T M Rangarajan  2 , Kuntal Bose  1 , Feba Benny  1 , Reshma Susan Ipe  1 , Sunil Kumar  1 , Neelima Kukreti  3 , Mohamed A Abdelgawad  4   5 , Mohammed M Ghoneim  6 , Hoon Kim  7 , Bijo Mathew  1
Affiliations
Review

"Click Chemistry": An Emerging Tool for Developing a New Class of Structural Motifs against Various Neurodegenerative Disorders

Amritha Manoharan et al. ACS Omega. .

Abstract

Click chemistry is a set of easy, atom-economical reactions that are often utilized to combine two desired chemical entities. Click chemistry accelerates lead identification and optimization, reduces the complexity of chemical synthesis, and delivers extremely high yields without undesirable byproducts. The most well-known click chemistry reaction is the 1,3-dipolar cycloaddition of azides and alkynes to form 1,2,3-triazoles. The resulting 1,2,3-triazoles can serve as both bioisosteres and linkers, leading to an increase in their use in the field of drug discovery. The current Review focuses on the use of click chemistry to identify new molecules for treating neurodegenerative diseases and in other areas such as peptide targeting and the quantification of biomolecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Different types of click reactions.
Figure 2
Figure 2
Representation of the copper-catalyzed azide–alkyne cycloaddition reaction.
Scheme 1
Scheme 1. Reagents and Conditions: (I) CuSO4, Sodium Ascorbate, tert-Butanol/H2O, 24 h, Room Temperature (rt)
Figure 3
Figure 3
Structure–activity relationship (SAR) of 1,2,3-triazoles toward MAO inhibition.
Scheme 2
Scheme 2. Reagents and Conditions: (I) CuSO4, Ascorbic Acid, Na2CO3, H2O/DMF, Overnight, rt; (II) Methyl Iodide (MeI), Sodium Hydride (NaH), Tetrahydrofuran (THF), 1.5–15 h, rt; (III) Phosphoric Acid (H3PO4), Methyl Chloride, 1.5–4 h, rt; (IV) Propargyl Bromide, Cesium Carbonate (Cs2CO3) Acetone, 2–15 h, rt; or 0 °C, 2–2.5 h; or 0 °C for 30 min and Then rt for 3 h
Scheme 3
Scheme 3. Reagents and Conditions: (V) Trimethylsilylacetylene, THF, n-BuLi, −78 °C, 30 min, and Then ZnBr2, THF, −78 to 0 C°; (VI) Silver Trifluoromethanesulfonate (AgOTf) and Methylchloride/MeOH/H2O Overnight, rt; (I) Methyl Azide, CuSO4·5H2O, Ascorbic Acid, Na2CO3, H2O/Dimethylformamide (DMF), Overnight, rt; (VII) LiAlH4, THF, Reflux, 2 h; (VIII) (Boc)2O, THF, rt; (II) MeI, NaH, THF, 60 °C, 4 h; (VII) LiAlH4, THF, 0 °C, Reflux, 72 h; (III) H3PO4, CH2Cl2, rt, 1.5–3 h; (IV) Propargyl Bromide, Cs2CO3, Acetone, 0 °C for 3.5 h or 0 °C for 30 min and Then rt for 3 h
Figure 4
Figure 4
SAR of N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines.
Scheme 4
Scheme 4. Reagents and Conditions: (IX) R1–Br, NaH, DMF, Reflux; (X) HBr, Acetic Acid, 115 °C, 15 h; (IV) Cs2CO3, DMF, Propargyl Bromide, 60 °C, 3 h; (I) ArCH2N3 or ArN3, CuSO4·5H2O, Sodium Ascorbate, THF–H2O (1:1), rt
Figure 5
Figure 5
SAR of harmine-conjugated 1,2,3-triazoles.
Scheme 5
Scheme 5. Reagents and Conditions: (I) CuSO4·5H2O, Sodium Ascorbate, CH3OH/H2O 1/4 1:1, 25 °C, 2 h; (XI) CH2Cl2, BBr3, CH3OH, 0 °C–rt
Figure 6
Figure 6
SAR of the hybrids of coumarin derivatives and hydroxypyridinones.
Scheme 6
Scheme 6. Reagents and Conditions: (I) CuSO4, Sodium Ascorbate, THF/H2O = 1:1, rt
Figure 7
Figure 7
SAR of azide-substituted flavones.
Scheme 7
Scheme 7. Reagents and Conditions: (XIII) Imidazole-1-sulfonyl Azide Hydrogen Sulfate, CuSO4, NaHCO3, MeOH/H2O; or BnCl, K2CO3, Acetone; (I) Terminal Alkyne (RC≡CH), CuSO4, Sodium Ascorbate, DMF, 100 °C under Microwave (MW)
Scheme 8
Scheme 8. Reagents and Conditions: (XIV) BnBr, K2CO3, EtOH, 90 °C; LiAlH4, DCM/THF, 70 °C, N2 (g); (XV) Azido Amino Acid, HBTU, DIPEA, DMF; (I) Phenylacetylene, CuSO4, Sodium Ascorbate, t-BuOH/H2O/DCM (1:1:1); (XVI) Morpholine/DCM (1:1); (XVII) Ac2O, Pyridine
Figure 8
Figure 8
SAR of aryl-1,2,3-triazolyl benzylpiperidine.
Scheme 9
Scheme 9. Reagents and Conditions: (IV) Propargyl Bromide, Cs2CO3, Acetonitrile, rt, 12 h; (XVIII) NH2OH·HCl, NaOH, MeOH, H2O, rt, 30 min; (XIX) Ac2O, Reflux, 8 h; (XX) Na2S2O4, H2O, 50–65 °C, 4 h; (XXI) DMF-DMA, Acetic Acid, Toluene, Reflux, 4 h; (XXII) Amine, Acetic Acid, Toluene, 60–110 °C, 4 h; (XXIII) Azide, DIPEA, CuI, THF, rt, 1–2 days
Figure 9
Figure 9
SAR of the quinazoline–triazole hybrids.
Scheme 10
Scheme 10. Reagents and Conditions: (XXIV) SOCl2, 80 °C; (XXV) 2-Aminobenzothiazole, 100 °C, MW, THF; (XXVI) K2CO3, Propane-1,3-dithiol, THF, 80 °C
Scheme 11
Scheme 11. Reagents and Conditions: (XXVII) EDCI, DMAP, DMF, rt, 5 min, then 2-Aminobenzothiazole, rt; (XXVIII) 3-Bromopropyne, K2CO3, MeCN, 90 °C; (XXIX) NaOH, MeOH/THF (1:1 v/v), rt; (XXVII) EDCI, DMAP, DMF, rt, 5 min, then 2-aminobenzothiazol; (I) CuSO4·5H2O, Sodium Ascorbate, DMF, rt
Scheme 12
Scheme 12. Reagents and Conditions: (I) CuSO4·5H2O, Sodium Ascorbate, DMF, rt
Scheme 13
Scheme 13. Reagents and Conditions: (I) CuSO4·5H2O, Sodium Ascorbate, DMF, rt
Scheme 14
Scheme 14. Click Reaction for the Synthesis of a Fluorescent Probe
Scheme 15
Scheme 15. Synthesis of Compound 36
Scheme 16
Scheme 16. Reaction of the Phototriggered Click Peptide
Scheme 17
Scheme 17. Reagents and Conditions: (I) CuSO4, Sodium Ascorbate
Figure 10
Figure 10
SAR of phenol–triazole ligand scaffold.
Scheme 18
Scheme 18. Synthesis of Compound 41
See this image and copyright information in PMC

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