Author(s):
Nikhil, Anchal Guleria, U. S. Mahadeva Rao, Lee Wan Zhen, Suganya Mahadeva Rao, Kalandar Ameer, Venketash Kumar Krishnamoorthy, Thanapakiam Ganeson, Kamini Vijeepallam, M. Bala Sundaram, Vinoth Kumar Selvaraj
Email(s):
raousm@unisza.edu.my
DOI:
10.52711/0974-360X.2025.00345 
Address:
Nikhil1, Anchal Guleria1, U. S. Mahadeva Rao2*, Lee Wan Zhen3, Suganya Mahadeva Rao4, Kalandar Ameer5, Venketash Kumar Krishnamoorthy6, Thanapakiam Ganeson6, Kamini Vijeepallam5, M. Bala Sundaram5, Vinoth Kumar Selvaraj7
1Laureate Institute of Pharmacy, Kathog, Jawalamukhi, Kangra, Himachal Pradesh, India.
2School of Basic Medical Sciences, Faculty of Medicine, Kampus Perubatan, Universiti Sultan Zainal Abidin (UniSZA), 20400 Kuala Terengganu, Malaysia.
3Exercise and Sports Science Programme, School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
4PEOPLE’S College of Dental Sciences and Research Centre, PEOPLE’s University, MP, Bhopal India.
5Unit of Biochemistry, Faculty of Medicine, AIMST University, Bedong, Kedah 08100, Malaysia.
6Unit of Pharmaceutical Technology, Faculty of Pharmacy, AIMST University, Bedong, Kedah 08100, Malaysia.
7Unit of Physiology, Faculty of Medicine, AIMST University, Bedong-Kedah 08100, Malaysia.
*Correspo
Published In:
Volume - 18,
Issue - 5,
Year - 2025
ABSTRACT:
K. Barry Sharpless invented click chemistry in 2001, and it has revolutionized drug development with its effective, diverse, and selective chemical synthesis. In fact, the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) process has become a crucial tool for drug-like particle assembly, functionalization of physiologically active mixtures, and accurate drug-biomolecule conjugation. Late-stage click chemistry applications span a number of industries, including prodrugs, antibody-drug conjugates (ADCs), and specific drug delivery systems including hydrogels and nanoparticles. Click reactions' high specificity and bio-orthogonality have increased therapeutic precision, lessening side effects and improving therapeutic outcomes. New reactions, such as sulfur-fluoride exchange (SuFEx) and strain-promoted azide-alkyne cycloaddition (SPAAC), are a part of emerging trends in click chemistry that expand the range of applications. Click chemistry has improved lead compound synthesis, made it easier to develop pharmacophore linkers, and produced bio isosteres to improve drug potency and metabolic stability in the drug discovery process. The method's role in creating cutting-edge treatments has also been highlighted by its contribution to the discovery of inhibitors for diseases like HIV, cancerous development, and bacterial infections. From early stage drug discovery to clinical development, click chemistry remains at the forefront of pharmaceutical analysis, highlighting its critical influence on ongoing drug development.
Cite this article:
Nikhil, Anchal Guleria, U. S. Mahadeva Rao, Lee Wan Zhen, Suganya Mahadeva Rao, Kalandar Ameer, Venketash Kumar Krishnamoorthy, Thanapakiam Ganeson, Kamini Vijeepallam, M. Bala Sundaram, Vinoth Kumar Selvaraj. Click chemistry in drug development recent trends and application. Research Journal of Pharmacy and Technology. 2025;18(5):2416-4. doi: 10.52711/0974-360X.2025.00345
Cite(Electronic):
Nikhil, Anchal Guleria, U. S. Mahadeva Rao, Lee Wan Zhen, Suganya Mahadeva Rao, Kalandar Ameer, Venketash Kumar Krishnamoorthy, Thanapakiam Ganeson, Kamini Vijeepallam, M. Bala Sundaram, Vinoth Kumar Selvaraj. Click chemistry in drug development recent trends and application. Research Journal of Pharmacy and Technology. 2025;18(5):2416-4. doi: 10.52711/0974-360X.2025.00345 Available on: https://rjptonline.org/AbstractView.aspx?PID=2025-18-5-68
REFERENCES:
1. Agrahari, A. K., Bose, P., Jaiswal, M. K., Rajkhowa, S., Singh, A. S., Hotha, S., and Tiwari, V. K. Cu (I)-catalyzed click chemistry in glycoscience and their diverse applications. Chemical Reviews. 2021; 121(13): 7638-7956.
2. Amna, B., and Ozturk, T. Click chemistry: A fascinating method of connecting organic groups. Organic Communications. 2021; 14(2): 120.
3. Aneja R, Rashad AA, Li H, et al. Peptide triazole inactivators of HIV-1 utilize a conserved two-cavity binding site at the junction of the inner and outer domains of Env gp120. J Med Chem. 2015; 58 (9): 3843–3858.
4. Arseneault, M., Wafer, C., and Morin, J. F. Recent advances in click chemistry applied to dendrimer synthesis. Molecules. 2015; 20(5): 9263-9294.
5. Arslan, M., Acik, G., and Tasdelen, M. A. The emerging applications of click chemistry reactions in the modification of industrial polymers. Polymer Chemistry. 2019; 10(28): 3806-3821.
6. Battigelli, A., Almeida, B., and Shukla, A. Recent advances in bioorthogonal click chemistry for biomedical applications. Bioconjugate Chemistry. 2022; 33(2): 263-271.
7. Bertrand HC, Schaap M, Baird L, et al. Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction. J Med Chem. 2015; 58(18): 7186–7194.
8. Bird, R. E., Lemmel, S. A., Yu, X., and Zhou, Q. A. Bioorthogonal chemistry and its applications. Bioconjugate Chemistry. 2021; 32(12): 2457-2479
9. Cañeque, T., Müller, S., and Rodriguez, R. Visualizing biologically active small molecules in cells using click chemistry. Nature Reviews Chemistry. 2018; 2(9): 202-215.
10. Caselli E, Romagnoli C, Vahabi R, et al. Click chemistry in lead optimization of boronic acids as β-lactamase inhibitors. J Med Chem. 2015; 58(14): 5445–5458.
11. Clavadetscher J, Hoffmann S, Lilienkampf A, et al. Copper catalysis in living systems and in situ drug synthesis. Angew Chem Int Ed Engl. 2016; 55(50): 15662–15666.
12. Devaraj NK. The future of bioorthogonal chemistry. ACS Cent Sci. 2018;4(8): 952–959.
13. Díaz JL, Christmann U, Fernández A, et al. Synthesis and structure activity relationship study of a new series of selective σ (1) receptor ligands for the treatment of pain: 4-aminotriazoles. J Med Chem. 2015; 58(5): 2441–2451.
14. Espeel, P., and Du Prez, F. E. “Click”-inspired chemistry in macromolecular science: matching recent progress and user expectations. Macromolecules. 2015; 48(1): 2-14.
15. Fang Z, Kang D, Zhang L, et al. Synthesis and biological evaluation of a series of 2-((1-substituted-1H-1,2,3-triazol-4-yl) methylthio)- 6-(naphthalen-1-ylmethyl) pyrimidin-4(3H)-one as potential HIV-1 inhibitors. Chem Biol Drug Des. 2015; 86(4): 614–618.
16. Farrer, N. J., and Griffith, D. M. Exploiting azide–alkyne click chemistry in the synthesis, tracking and targeting of platinum anticancer complexes. Current Opinion in Chemical Biology. 2020; 55: 59-68.
17. Gao P, Sun L, Zhou J, et al. Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approach. Expert Opin Drug Discov. 2016; 11(9): 857–871.
18. Ghamat, S. N., Talebpour, Z., and Mehdi, A. Click reactions: Recent trends in preparation of new sorbents and stationary phases for extraction and chromatographic applications. TrAC Trends in Analytical Chemistry. 2019; 118: 556-573.
19. Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017; 21(Suppl 1): S110–S124.
20. Haldón E, Nicasio MC, Pérez PJ. Copper-catalysed azide-alkyne cycloadditions (CuAAC): an update. Org Biomol Chem. 2015; 13(37): 9528–9550.
21. Hong, T., Liu, W., Li, M., and Chen, C. Click chemistry at the microscale. Analyst. 2019; 144(5): 1492-1512.
22. Jiang, X., Hao, X., Jing, L., Wu, G., Kang, D., Liu, X., and Zhan, P. Recent applications of click chemistry in drug discovery. Expert Opinion on Drug Discovery. 2019; 14(8): 779-789.
23. Kang D, Zhang H, Zhou Z, et al. First discovery of novel 3-hydroxyquinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold ‘refining approach. Bioorg Med Chem Lett. 2016; 26(21): 5182–5186.
24. Kaur, J., Saxena, M., and Rishi, N. An overview of recent advances in biomedical applications of click chemistry. Bioconjugate Chemistry. 2021; 32(8): 1455-1471.
25. Kern FT, Wanner KT. Generation and screening of oxime libraries addressing the neuronal GABA transporter GAT1. Chem Med Chem. 2015; 10(2): 396–410.
26. Lapinsky, D. J., and Johnson, D. S. Recent developments and applications of clickable photoprobes in medicinal chemistry and chemical biology. Future Medicinal Chemistry. 2015; 7(16): 2143-2171.
27. Lee H, Lee JK, Min SJ, et al. Copper(I)-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles from azidoformates and aryl terminal alkynes. J Org Chem. 2018; 83(8): 4805–4811.
28. Li, X., and Xiong, Y. Application of “click” chemistry in biomedical hydrogels. ACS Omega. 2022; 7(42): 36918-36928.
29. Meghani, N. M., Amin, H. H., and Lee, B. J. Mechanistic applications of click chemistry for pharmaceutical drug discovery and drug delivery. Drug Discovery Today. 2017; 22(11): 1604-1619.
30. Meldal, M., and Diness, F. Recent fascinating aspects of the CuAAC click reaction. Trends in Chemistry. 2020; 2(6): 569-584.
31. Meyer, J. P., Adumeau, P., Lewis, J. S., and Zeglis, B. M. Click chemistry and radiochemistry: the first 10 years. Bioconjugate Chemistry. 2016; 27(12): 2791-2807.
32. Mohammed I, Kummetha IR, Singh G, et al. 1,2,3-Triazoles as amide bio isosteres: discovery of a new class of potent HIV-1 Vif antagonists. J Med Chem. 2016; 59(16): 7677–7682.
33. Musumeci, F., Schenone, S., Desogus, A., Nieddu, E., Deodato, D., and Botta, L. Click chemistry, a potent tool in medicinal sciences. Current Medicinal Chemistry. 2015; 22(17): 2022-2050.
34. Ouyang, T., Liu, X., Ouyang, H., and Ren, L. Recent trends in click chemistry as a promising technology for virus-related research. Virus Research. 2018; 256: 21-28.
35. Palmer D, Jpl G, Hansen L V, et al. Click-chemistry-mediated synthesis of selective melanocortin receptor 4 agonists. J Med Chem. 2017; 60(21): 8716–8730.
36. Rashad AA, Kalyana Sundaram RV, Aneja R, et al. Macrocyclic envelope glycoprotein antagonists that irreversibly inactivate HIV-1 before host cell encounter. J Med Chem. 2015; 58(18): 7603–7608.
37. Rodríguez, D. F., Moglie, Y., Ramírez-Sarmiento, C. A., Singh, S. K., Dua, K., and Zacconi, F. C. Bio-click chemistry: a bridge between biocatalysis and click chemistry. RSC advances. 2022; 12(4): 1932-1949.
38. Singh, M. S., Chowdhury, S., and Koley, S. Advances of azide-alkyne cycloaddition-click chemistry over the recent decade. Tetrahedron. 2016; 72(35): 5257-5283.
39. Testa C, Papini AM, Chorev M, et al. Copper-catalyzed azide-alkyne cycloaddition (CuAAC)-mediated macrocyclization of peptides: impact on conformation and biological activity. Curr Top Med Chem. 2018; 18(7): 591–610.
40. Tiwari VK, Mishra BB, Mishra KB, et al. Cu-catalyzed click reaction in carbohydrate chemistry. Chem Rev. 2016; 116(5): 3086–3240.
41. Wang X, Huang B, Liu X, et al. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. Drug Discov Today. 2016; 21(1): 118–132.
42. Wang Y, Zhu J, Zhang L. Discovery of cell-permeable O-GlcNAc transferase inhibitors via tethering in situ click chemistry. J Med Chem. 2017; 60(1): 263–272.
43. Wong ILK, Zhu X, Chan KF, et al. Discovery of novel flavonoid dimers to reverse multidrug resistance protein 1 (MRP1, ABCC1) mediated drug resistance in cancers using a high throughput platform with “Click Chemistry”. J Med Chem. 2018; 61(22): 9931–9951.
44. Wu G, Zalloum WA, Meuser ME, et al. Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library. Eur J Med Chem. 2018; 158: 478–492.
45. Wu Y, Jiang Z, Li Z, et al. Click Chemistry-based discovery of [3-hydroxy-5-(1H-1,2,3-triazol-4-yl) picolinoyl] glycines as orally active hypoxia-inducing factor prolyl hydroxylase inhibitors with favorable safety profiles for the treatment of anemia. J Med Chem. 2018; 61(12): 5332–5349. In this paper, a triazole compound was identified as a promising candidate for the treatment of renal anemia.
46. Wurz RP, Dellamaggiore K, Dou H, et al. A “click chemistry platform” for the rapid synthesis of bispecific molecules for inducing protein degradation. J Med Chem. 2018; 61(2): 453–461.
47. Yao, T., Xu, X., and Huang, R. Recent advances about the applications of click reaction in chemical proteomics. Molecules, 2021; 26(17): 5368.
48. Yoon, H. Y., Lee, D., Lim, D. K., Koo, H., and Kim, K. Copper‐free click chemistry: applications in drug delivery, cell Tracking, and tissue engineering. Advanced Materials. 2022; 34(10): 2107192.
49. Zakharova EA, Shmatova OI, Kutovaya IV, et al. Synthesis of macrocyclic peptidomimetics via the Ugi-click-strategy. Org Biomol Chem. 2019 Mar 27; 17(13): 3433–3445.
50. Zeng DY, Kuang GT, Wang SK, et al. Discovery of novel 11-triazole substituted benzofuro[3,2-b] quinolone derivatives as c-myc G-quadruplex specific stabilizers via click chemistry. J Med Chem. 2017; 60(13): 5407–5423.