Click chemistry-aided drug discovery: A retrospective and prospective outlook

Solid Phase Synthesis and TAR RNA-Binding Activity of Nucleopeptides Containing Nucleobases Linked to the Side Chains via 1,4-Linked-1,2,3-triazole

“…The popularity of click chemistry, especially the CuAAC variant, and the ease of formation of the triazole ring have made the design and synthesis of new systems containing this system an important branch of synthetic organic chemistry [ 57 ]. In many cases, the newly obtained triazole derivatives of known chemical structures showed greater biological activity than their unmodified counterparts [ 57 , 58 , 59 ].…”

“…The popularity of click chemistry, especially the CuAAC variant, and the ease of formation of the triazole ring have made the design and synthesis of new systems containing this system an important branch of synthetic organic chemistry [ 57 ]. In many cases, the newly obtained triazole derivatives of known chemical structures showed greater biological activity than their unmodified counterparts [ 57 , 58 , 59 ]. In most cases, the triazole ring was introduced into small-molecule compounds, although examples of the introduction of this system into large macromolecules such as peptides or nucleic acids are known [ 60 , 61 , 62 ].…”

Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

“…188 These alkynes can be converted into triazoles through "click" reactions, serving as linkers to connect with other pharmacophores. 25,26 This enables the development of triazole hybrids with the potential to maintain or improve anticancer activities compared to the parent drugs. Additionally, these triazole hybrids may contribute to overcoming drug resistance to some extent (Figure 37A).…”

“…Certain anticancer drugs, such as erlotinib and icotinib, feature terminal alkynes in their structures . These alkynes can be converted into triazoles through “click” reactions, serving as linkers to connect with other pharmacophores. , This enables the development of triazole hybrids with the potential to maintain or improve anticancer activities compared to the parent drugs. Additionally, these triazole hybrids may contribute to overcoming drug resistance to some extent (Figure A). , The erlotinib derivative bearing a 1,2,3-triazole linker effectively suppresses cell proliferation including cancer cells H1650 and KYSE450 as well paclitaxel-resistant cell H1650TR and KYSE450TR superior to erlotinib .…”

“…Among the structurally related compounds, 1,2-dihydro-3 H -1,2,4-triazol-3-one and 4 H -benzo­[ f ]­[1,2,4]­triazolo­[4,3- a ]­[1,4]­diazepine are prominent. , Furthermore, this paper summarizes the top 100 triazole-related agents from clinical trials before 2020 (Figure ). Both 1,2,4-triazole and 1,2,3-triazole have garnered attention in drug design, particularly 1,2,4-triazole, which serves as a key pharmacophore extensively employed in the design of small molecule inhibitors such as antifungal agents and aromatase inhibitors. , Notably, these drug structures often feature 1,2,4-triazole at the terminal end, typically with substituents connected to the N1 position, such as letrozole, anastrozole, and fluconazole, primarily due to the mechanism of action involving the inhibition of cytochrome P450 (CYP450) and its family members by antifungal and aromatase inhibitors. , The lone pair electrons of the triazoles within the drug mimic a heme iron–nitrogen coordinate bond, thereby inhibiting the active sites of various enzymes within the CYP family. , In FDA-approved drug structures, 1,2,3-triazole is commonly utilized in dual orexin receptor antagonists (DORAs) for the treatment of insomnia, including daridorexant and suvorexant. , Despite the considerable interest in both 1,2,3-triazole and 1,2,4-triazole as potential anticancer pharmacophores for drug design, no anticancer drugs containing 1,2,3-triazole have been approved by the FDA, while several compounds containing 1,2,4-triazoles have entered clinical treatments. , 1,2,3-Triazole is favored in drug synthesis due to its straightforward synthetic methods, particularly with the widespread application of “click” chemistry and bioorthogonal coupling reactions in the field of medicinal chemistry, notably with 1,2,3-triazole serving as a linker in “click” chemistry-related drugs. − Attempts have been made to improve the shortcomings of traditional small molecule inhibitors by designing proteolysis targeting chimeras (PROTACs) and hydrophobic tagging (HyT) degraders as well as peptide–drug conjugates (PDCs) containing 1,2,3-triazole linkers using “click” chemistry. − Bioorthogonal coupling reaction methods enable real-time detection of PDCs, laying the foundation for further development and maturation of PDCs . Furthermore, 1,4-disubstituted 1,2,3-triazole scaffolds as amide bioisosteres, along with trans- amide bond isosteres, have found wide applications. , Replacing amide bonds with 1,4-disubstituted 1,2,3-triazoles in certain anticancer drugs such as vismodegib significantly improves the stability and even enhances antitumor activity .…”