Cu(I)-catalyzed Azide-alkyne Cycloaddition Research Articles

Click Synthesis of Triazole Polymers Based on Lignin-Derived Metabolic Intermediate and Their Strong Adhesive Properties to Cu Plate

2-Pyrone-4,6-dicarboxylic acid (PDC) is a chemically stable metabolic intermediate of lignin that can be produced on a large scale by transforming bacteria. Novel biomass-based polymers based on PDC were synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and fully characterized by nuclear magnetic resonance, infrared spectroscopies, thermal analysis, and tensile lap shear strength measurements. The onset decomposition temperatures of these PDC-based polymers were all above 200 °C. In addition, the PDC-based polymers exhibited strong adhesive properties to various metal plates, with the highest adhesion to a copper plate of 5.73 MPa. Interestingly, this result was in contrast to our previous findings that PDC-based polymers weakly adhere to copper. Furthermore, when bifunctional alkyne and azide monomers were polymerized in situ under hot-press conditions for 1 h, the resulting PDC-based polymer displayed a similar adhesion to a copper plate of 4.18 MPa. The high affinity of the triazole ring to copper ions improved the adhesive ability and selectivity of the PDC-based polymers to copper while still maintaining the strong adhesive ability to other metals, which is conducive to enhancing the versatility of PDC-based polymers as adhesives.

Click-derived multifunctional metal complexes for diverse applications.

The Click reaction that involves Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) serves as the most potent and highly dependable tool for the development of many complex architectures. It has paved the way for the synthesis of numerous drug molecules with enhanced synthetic flexibility, reliability, specificity and modularity. It is all about bringing two different molecular entities together to achieve the required molecular properties. The utilization of Click chemistry has been well demonstrated in organic synthesis, particularly in reactions that involve biocompatible precursors. In pharmaceutical research, Click chemistry is extensively utilized for drug delivery applications. The exhibited bio-compatibility and dormancy towards other biological components under cellular environments makes Click chemistry an identified boon in bio-medical research. In this review, various click-derived transition metal complexes are discussed in terms of their applications and uniqueness. The scope of this chemistry towards other streams of applied sciences is also discussed.

Computational studies of the CuAAC reaction mechanism with diimine and phosphorus ligands for the synthesis of 1,4-disubstituted 1,2,3-triazoles

The Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions with diimine and phosphorus ligands have been studied using DFT calculations in order to understand the effect of the nature of the ligands on the catalytic cycle for the formation of the 1,4-regioisomer.

Radiochemical Synthesis of 4-[18F]FluorobenzylAzide and Its Conjugation with EGFR-Specific Aptamers

Central nervous system tumors related to gliomas are of neuroectodermal origin and cover about 30% of all primary brain tumors. Glioma is not susceptible to any therapy and surgical attack remains one of the main approaches to its treatment. Preoperative tumor imaging methods, such as positron emission tomography (PET), are currently used to distinguish malignant tissue to increase the accuracy of glioma removal. However, PET is lacking a specific visualization of cells possessing certain molecular markers. Here, we report an application of aptamers to enhancing specificity in imaging tumor cells bearing the epidermal growth factor receptor (EGFR). Glioblastoma is characterized by increased EGFR expression, as well as mutations of this receptor associated with active division, migration, and adhesion of tumor cells. Since 2021, EGFR has been included into the WHO classification of gliomas as a molecular genetic marker. To obtain conjugates of aptamers GR20 and GOL1-specific to EGFR, a 4-[18F]fluorobenzylazide radiotracer was used as a synthon. For the production of the synthon, a method of automatic synthesis on an Eckert & Ziegler research module was adapted and modified using spirocyclic iodonium ylide as a precursor. Conjugation of 4-[18F]fluorobenzylazide and alkyne-modified aptamers was carried out using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with/without the TBTA ligand. As a result, it was possible to obtain 18F-labelled conjugates with 97% radiochemical purity for [18F]FB-GR20 and 98% for [18F]FB-GOL1. The obtained conjugates can be used for further studies in PET analysis on model animals with grafted glioblastoma.

Ultrasound-assisted synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives using Fe3O4@CQD@CuI as a novel nanomagnetic catalyst

The magnetic nanoparticles coated with carbon quantum dot and copper (I) iodide (Fe3O4@CQD@CuI) were used as eco-friendly heterogeneous Lewis / Brønsted acid sites and Cu (I) nanocatalysts. In the first step, it was applied in the synthesis of kojic acid-based dihydropyrano[3,2-b]pyran derivatives in a three-component reaction and in the second step, as a recyclable catalyst for the synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives in the CuI-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The catalyst was characterized fully by using the different techniques including fourier transform infrared spectroscopy (FT-IR), elemental mapping analysis, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), X-ray spectroscopy (EDX), transmission electron microscopy (TEM), thermal gravimetric (TG) and value-stream mapping (VSM) methods. The final synthesized derivatives were identified by 1H- and 13C-NMR spectroscopy.

H3TPAN-Triazole-Bn-NH2: Tripicolinate Clicked-Bifunctional Chelate for [225Ac]/[111In] Theranostics.

A new, high-denticity, bifunctional ligand─H3TPAN-triazole-Bn-NH2─has been synthesized and studied in complexation with [225Ac]Ac3+ and [111In]In3+ for radiopharmaceutical applications. The bifunctional chelator is readily synthesized, using a high-yielding four-step prep, which is highly adaptable and allows for straightforward incorporation of different covalent linkers using CuI-catalyzed alkyne-azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of H3TPAN-triazole-Bn-NH2 with La3+ and In3+ metal ions show the formation of a single, asymmetric complex with each ion in solution, corroborated by density functional theory (DFT) calculations. Radiolabeling studies with [225Ac]Ac3+ and [111In]In3+ showed highly effective complexation, achieving quantitative radiochemical conversions at low ligand concentrations (<10-6 M) under mild conditions (RT, 10 min), which is further accompanied by high stability in human serum. The bioconjugate─H3TPAN-triazole-Bn-Aoc-Pip-Nle-CycMSHhex─was prepared for targeting of MC1R-positive tumors, and the corresponding 111In-radiolabeled tracer was studied in vivo. SPECT/CT and biodistribution studies in C57BL/6J mice bearing B16-F10 tumors were performed, with the radiotracer showing good in vivo stability; tumor uptake was achieved. This work highlights a new promising and versatile bifunctional chelator, easily prepared and encouraging for 225Ac/111In theranostics.

A Motor-Based Carbonaceous Nanocalabash Catalyst for Deep-Layered Bioorthogonal Chemistry.

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been widely regarded as a promising avenue in bioorthogonal chemistry. The emerging heterogeneous copper catalysts have been developed with a series of exciting applications such as in situ activation of prodrugs because of their excellent stability and biocompatibility. However, due largely to the complex biophysical barriers in living organisms, most synthetic bioorthogonal drugs cannot penetrate deep pathological tissues. Especially in biofilm-associated infections, the biofilms severely block the penetration of traditional antimicrobial agents and increase the antibiotic resistance, which makes it extremely difficult to eliminate the biofilms. Inspired by self-propelled biological motors, such as enzymes, herein, we develop a NIR light-controllable carbonaceous nanocalabash (CNC) motor catalyst with good biocompatibility for active targeted synthesis of drugs inside the biofilms as a robust general-purpose bioorthogonal platform. Under the NIR laser, the CNC motor catalysts display a rapid autonomous motion and generate active molecules in the deep biofilm layers, removing the biofilms and eradicating the shielded bacteria. Our work will shed light on developing a robust bioorthogonal platform for active targeted synthesis of drugs in deep-layered living systems.

H4picoopa─Robust Chelate for 225Ac/111In Theranostics.

The nuclear decay characteristics of 225Ac (Eα = 5-8 MeV, linear energy transfer (LET) = ∼100 keV/μm, t1/2 = 9.92 days) are well recognized as advantageous for the treatment of primary and metastatic tumors; however, suitable chelation systems are required, which can accommodate this radiometal. Since 225Ac does not possess any suitable low-energy, high abundance γ-ray emissions for nuclear imaging, there is a clear need for the development of other companion radionuclides with similar coordination characteristics and comparable half-lives, which can be applied in diagnostics. H4picoopa was designed and executed as a high-denticity ligand for chelation of [225Ac]Ac3+, and the complexation characteristics have been explored through nuclear magnetic resonance (NMR) spectroscopy, solution thermodynamic stability studies, and radiolabeling. The ligand shows highly favorable complexation with La3+ (pM = 17.6), Lu3+ (pM = 21.3), and In3+ (pM = 31.2) and demonstrates effective radiolabeling of both [225Ac]Ac3+ and [111In]In3+ ions achieving quantitative radiochemical conversions (RCCs) under mild conditions (RT, 10 min), accompanied by high serum stability (>97% radiochemical purity (RCP) over 6 days). A bifunctional analogue of H4picoopa was synthesized and conjugated to the Pip-Nle-CycMSHhex peptide for targeting of MC1R positive melanoma tumors. In vivo single-photon emission computed tomography (SPECT) and biodistribution studies of the 111In-radiolabeled bioconjugate in mice bearing B16-F10 tumors showed good radiotracer stability, although improved tumor targeting could not be achieved for imaging purposes. This work highlights H4picoopa as a very promising platform for application of [225Ac]Ac3+ and [111In]In3+ as a theranostic pair and allows great versatility for the incorporation of other directing vectors. The logical synthetic approach reported here for bifunctional H4picoopa, involving an azide-functionalized covalent linker and CuI-catalyzed alkyne-azide cycloaddition, allows for ease of optimization of bioconjugate pharmacokinetics and will be valuable for further radiopharmaceutical applications moving forward.

Preparation of nickel-chelated iminodiacetate-functionalized macroporous agarose monolith using modular and clickable building blocks for affinity separation of histidine-tagged recombinant proteins

Selective separation and purification of protein from complex medium is required to completely investigate the structure and function of the target protein. In this study, a composite macroporous agarose monolith containing iminodiacetate-chelated Ni2+ ligands was synthesized for selective separation and purification of histidine-tagged recombinant proteins. The large and interconnected pores in the monolith enabled fast binding of proteins with high matrix tolerance in treating complex mediums. To realize the selective protein binding, the iminodiacetate was directly conjugated to epoxy-functionalized agarose monolith via simple chemical reactions between epoxy and imino groups. After chelated Ni2+, the composite monolith could bind histidine-tagged recombinant proteins through the coordination interaction between transition metal ions and the imidazole ring of histidine. To further increase the binding capacities of the monolith, a hydrophilic intermediate polymer chain containing multiple iminodiacetate immobilization sites was conjugated to the azide-functionalized agarose monolith via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The morphology and chemical composition of the composite agarose monolith were characterized systematically. The protein binding capacities of the obtained composite agarose monolith were subsequently investigated. The binding capacities of the composite agarose monolith towards the model proteins Gp10 and Lys84 were 0.93 and 0.51 mg/mL, respectively. The protein binding of the composite agarose monolith could be manipulated by adjusting the temperature and concentrations of imidazole. These results demonstrate that the composite agarose monolith could be used as an affinity medium for rapid separation and purification of histidine-tagged recombinant proteins from biological samples.

DFT-Guided Discovery of Ethynyl-Triazolyl-Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling.

We report the density functional theory (DFT) guided discovery of ethynyl-triazolyl-phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using CuI -catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl-phosphinate. ETP-reagents were used to obtain fluorescent peptide-conjugates for receptor labelling on live cells and a stable and a biologically active antibody-drug-conjugate. Moreover, we were able to incorporate ETP-electrophiles into an azide-containing ubiquitin under native conditions and demonstrate their potential in protein-protein conjugation. Finally, we showcase the excellent cysteine-selectivity of this new class of electrophile in mass spectrometry based, proteome-wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules.

ABC-Type, Bola-Form Giant Surfactants: Synthesis and Self-Assembly.

Due to the fast phase separation kinetics and small feature size, the self-assembly of giant molecules has attracted lots of attention. However, there is not much study on multicomponent giant surfactants. In this work, through a modular synthetic strategy, different polyhedral oligomeric silsesquioxane (POSS)-based molecular nanoparticles are installed with diverse functionalities (hydrophobic octavinyl POSS (VPOSS), hydrophilic dihydroxyl-functionalized POSS (DPOSS), and omniphobic perfluoroalkyl-chain-functionalized POSS (FPOSS)) on the ends of one polystyrene (PS) chain to build up a series of triblock bola-form giant surfactants denoted as XPOSS-PSn -FPOSS (X represents V or D). The target molecules are prepared by a combination of atom transfer radical polymerization (ATRP), esterification, as well as Cu(I)-catalyzed azide-alkyne cycloaddition(CuAAC) and thiol-ene "click" reactions. These macromolecules are thoroughly characterized by combined technologies including nuclear magnetic resonance(NMR), size exclusion chromatography (SEC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analyses. It is revealed by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) that VPOSS-PSn -FPOSS adopts a two-phase separation scenario where VPOSS and POSS are segregated in one phase. DPOSS-PSn -FPOSS with a third hydrophilic DPOSS shows a three-phase separation scenario, where highly ordered phase structures are difficult to develop owing to the competition of mutual phase separation processes and may be trapped in kinetically metastable states.

Ultrafast synthesis of dialkyne-functionalized polythioether and post-polymerization modification via click chemistry

Herein, we prepare a polythioether with double “clickable” alkyne groups in each repeating unit via an extremely rapid polymerization method and combine it with Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to construct new topological polymers. A monomer having both electron-deficient and electron-rich dual alkyne functionalities was synthesized and subsequently reacted with 1,6-hexanedithiol (HDT) using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst, and the reaction proceeded at room temperature for 1 min to give polythioether P1. The obtained polymer was then used as a polymer platform and reacted with a variety of azide compounds to modify the pendant alkynes via CuAAC reaction. The post-polymerization modification (PPM) studies have also been shown to be rapid as the reactions reached completion in 1 h. All synthesized polymers were analyzed using various spectroscopic methods and the results confirmed that quantitative “click” reaction efficiency was achieved in each reaction. It is believed the presented strategy not only provides a time-saving approach for both polymer synthesis and PPM, but also brings a new insight to impart the desired functionalities to a polymer chain with CuAAC “click” chemistry. Thus, a new type of polymer structure that can be prepared rapidly and undergoes fast PPM has been introduced to polymer chemistry with this study. • A Polythioether with clickable pendant units has been synthesized extremely rapidly in 1 min. • Post-polymerization modification (PPM) via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction has been successfully carried out. • Quantitative “click” reaction efficiency has been achieved in all cases. • Time- and energy-saving polymerization and PPM method have been developed.

Selective oligosaccharide recognition with phenylboronic acid through Cu(I)-catalysed click imprinted surfaces

With the emerging role of glycans as potential diagnostic markers of disease, highly selective diagnostic platforms must be developed to realise the clinical value of irregular glycan expression patterns. Overcoming chemical and structural homogeneity between oligosaccharide structures however remains a significant challenge, which largely rests on the capability to develop materials embedding precise carbohydrate recognition. Herein we report a surface imprinting strategy that takes advantage of the high yield Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) click reaction to achieve oligosaccharide imprinted cavities featuring precisely organized phenylboronic acid (PBA) motifs. Central to the construction of the imprinted surface was the choice of a foundation alkyne-terminated monolayer of a long alkyl chain to impart a high surface click efficiency of the PBA motif. By pre-forming and clicking an oligosaccharide:PBA complex onto the alkyne-terminated monolayer and capping the free space, selective oligosaccharide imprinted cavities were formed with low millimolar dissociation constants.

Functionalization of Covalent Organic Frameworks with DNA via Covalent Modification and the Application to Exosomes Detection.

The functionalization of covalent organic frameworks (COFs) with biomacromolecules can extend their functions, which is the premise of their application in biomedical research. However, strategies to functionalize COFs with biomacromolecules, which can ensure the stability in complex medium and minimize the undesired effects, are still lacking. In this work, we have proposed a strategy to functionalize COFs with DNA by covalently linking DNA to the functional group on the COF surface through Cu(I)-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The as-prepared DNA-functionalized COFs (DNA-COFs) can exhibit good hybridization ability and cargo loading ability; thus, we have designed a DNA-COF-based nanoprobe and then fabricated an electrochemical biosensor for the detection of exosomes. In this design, the functionalization with DNA enables COFs to recognize and capture exosomes, and the encapsulation of a large number of methylene blue (MB) in COFs facilitates signal amplification, which can enhance the sensitivity of the biosensor. Moreover, by simply replacing the oligonucleotide sequences, the strategy proposed here can generally be used to build different DNA-COFs with diverse functions for broader biomedical applications.

Advance of click chemistry in anion exchange membranes for energy application

AbstractClick chemistry has attracted tremendous attention in polymer synthesis due to its high efficiency, considerable yield, and simple synthesis/work‐up procedures. Among the various functional polymer materials prepared by click chemistry, anion exchange membrane (AEM) is a kind of polyelectrolyte which contains cations attached to the polymer skeleton. Click chemistry not only provides facile pathways for the preparation of AEMs but also generates diverse architectures of AEMs with robust performance. The commonly used click chemistry in AEMs consists of: (i) Diels‐Alder reaction, (ii) thiol‐ene, and (iii) Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC). This review will focus on the advance of click chemistry in the preparation of AEMs, especially synthetic approaches for different AEMs and their corresponding application in energy‐related fields, such as fuel cells, redox flow battery, electrodialysis, and so on.

Extracellular Electron Transfer Enables Cellular Control of Cu(I)-Catalyzed Alkyne-Azide Cycloaddition.

Extracellular electron transfer (EET) is an anaerobic respiration process that couples carbon oxidation to the reduction of metal species. In the presence of a suitable metal catalyst, EET allows for cellular metabolism to control a variety of synthetic transformations. Here, we report the use of EET from the electroactive bacterium Shewanella oneidensis for metabolic and genetic control over Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC). CuAAC conversion under anaerobic and aerobic conditions was dependent on live, actively respiring S. oneidensis cells. The reaction progress and kinetics were manipulated by tailoring the central carbon metabolism. Similarly, EET-CuAAC activity was dependent on specific EET pathways that could be regulated via inducible expression of EET-relevant proteins: MtrC, MtrA, and CymA. EET-driven CuAAC exhibited modularity and robustness in the ligand and substrate scope. Furthermore, the living nature of this system could be exploited to perform multiple reaction cycles without regeneration, something inaccessible to traditional chemical reductants. Finally, S. oneidensis enabled bioorthogonal CuAAC membrane labeling on live mammalian cells without affecting cell viability, suggesting that S. oneidensis can act as a dynamically tunable biocatalyst in complex environments. In summary, our results demonstrate how EET can expand the reaction scope available to living systems by enabling cellular control of CuAAC.

Visualizing an Allosteric Intermediate Using CuAAC Stabilization of an NMR Mixed Labeled Dimer.

Homodimers are the most abundant type of enzyme in cells, and as such, they represent the most elemental system for studying the phenomenon of allostery. In these systems, in which the allosteric features are manifest by the effect of the first binding event on a similar event at the second site, the most informative state is the asymmetric singly bound (lig1) form, yet it tends to be thermodynamically elusive. Here we obtain milligram quantities of lig1 of the allosteric homodimer, chorismate mutase, in the form of a mixed isotopically labeled dimer stabilized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between the subunits. Below, we outline several critical steps required to generate high yields of both types of unnatural amino acid-containing proteins and overcome multiple pitfalls intrinsic to CuAAC to obtain high yields of a highly purified, fully intact, active mixed labeled dimer, which provides the first glimpse of the lig1 intermediate. These data not only will make possible NMR-based investigations of allostery envisioned by us but also should facilitate other structural applications in which specific linkage of proteins is helpful.

A click-induced fluorescence-quenching sensor based on gold nanoparticles for detection of copper(Ⅱ) ion and ascorbic acid

Gold nanoparticles (AuNPs), as one of the major tools of fluorescence-quenching sensors, have been widely used in biochemical analysis through fluorescence resonance energy transfer (FRET) effect. With the development of chemistry and biochemistry, reaction-based fluorescent sensors have attracted increasing attention because of their unique selectivity, high sensitivity and rapid detection. Here we report a click-induced fluorescence-quenching sensor based on AuNPs for detection of copper ion (Cu2+) and ascorbic acid (AA). A fluorescent dye Rhodamine B-(CH2CH2O)4-azide (RB-PEG4-N3) is conjugated to the surface of AuNPs via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in the presence of Cu2+ and AA, leading to the fluorescence quenching of Rhodamine B. The sensor responds quickly (within less than 3 min). The fluorescent intensity linearly correlates with the concentration of Cu2+ in the range of 0–108 μM. The limit of detection (LOD) for Cu2+ is 5.8 μM. The concentration range for detection of AA is 0–3 mM. The LOD for AA is 0.13 mM. In addition, the application of the sensor is verified by performing detection in real samples such as fresh orange, juice, VC tablet, and lake water. This work expands the application of AuNPs-based fluorescence-quenching sensors for multi-component detection.

New 1,2,3-triazole linked flavonoid conjugates: Microwave-assisted synthesis, cytotoxic activity and molecular docking studies

The present study was carried out in an attempt to synthesize, under classical and microwave irradiation conditions, a new class of cytotoxic 1,2,3-triazole linked flavonols hybrids by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to afford, in good yields (78-93%), 24 compounds 1′a-i, 2′a-h and 3′a-g, using three previously synthesized highly cytotoxic poly-halogenated flavonoids 1-3. The structures of the newly synthesized compounds were established by 1H NMR, Jmod and ESI-HRMS. The prepared cycloadduct linked flavonols were evaluated for their cytotoxic activity against the human cell lines HCT-116 (Human colon carcinoma), MCF-7 (Human breast carcinoma) and OVCAR-3 (human ovarian carcinoma). The results showed that the cycloadducts 1′f, 1′g and 2′h against HCT-116 and 1′c, 2′g against OVCAR-3 were found to be the highest cytotoxic agents with IC50 values < 3.0 µM, therefore, they may serve as a promising lead candidate for further investigation. The probable binding modes of the most active compounds were explored and further verified using molecular dynamics simulation.

An Overview of Recent Advances in Biomedical Applications of Click Chemistry.

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is a modular and bio-orthogonal approach that is being adopted for the efficient synthesis of organic and bioorganic compounds. It leads to the selective formation of 1,4-disubstituted 1,2,3-triazole units connecting readily accessible building blocks via a stable and biocompatible linkage. The vast array of the bioconjugation applications of click chemistry has been attributed to its fast reaction kinetics, quantitative yields, minimal byproducts, and high chemospecificity and regioselectivity. These combined advantages make click reactions quite suitable for the lead identification and the development of pharmaceutical agents in the fields of medicinal chemistry and drug discovery. In this review, we have outlined the key aspects, the mechanistic details and merits and demerits of the click reaction. In addition, we have also discussed the recent pharmaceutical applications of click chemistry, ranging from the development of anticancer, antibacterial, and antiviral agents to that of biomedical imaging agents and clinical therapeutics.