Azide-alkyne Cycloaddition Reaction Research Articles

Azobenzene-Attached (NHC)Gold(I) and (NHC)Copper(I) Complexes as Photoswitchable Catalysts.

Photoswitchable (pre)catalysts, N,N'-bis-azobenzene-based (NHC)gold(I) and N,N'-bis-azobenzene-derived (NHC)copper(I) complexes are reported. Trans to cis isomerization of the attached photoswitchable moieties in the Au(I) complex enables four-fold decrement in the rate of oxazoline formation reaction. Whereas the progress of the copper(I) catalyzed, azide-alkyne cycloaddition reaction gets reduced by at least threefold. Alternate exposure to UV and blue light could easily toggle the rate of reactions remotely. The catalytic activity of thermodynamically stable trans-trans isomers is found to be similar to the common N-aryl substituted NHC-Au/Cu(I) complexes. NHC-Au(I) and -Cu(I) compounds bearing (trans)azobenzene moieties were characterized by X-ray diffraction. Photoswitching, recyclability studies, and the metastable isomer's thermal half-life in both complexes were studied via UV-visible spectroscopy. Whereas the extent of photoswitching and concomitant formation of geometrical isomers were investigated by using 1H-NMR spectroscopic study. Calculated percentage buried volumes of the three geometrical isomers show the trend trans-trans<trans-cis<cis-cis.

Antibody-targeted T cells and natural killer cells for cancer immunotherapy

BackgroundAdoptive cell cancer therapies aim to re-engineer a patient’s immune cells to mount an anti-cancer response. Chimeric antigen receptor T and natural killer cells have been engineered and proved successful in treating some cancers; however, the genetic methods for engineering are laborious, expensive, and inefficient and can cause severe toxicities when they over-proliferate.ResultsWe examined whether the cell-killing capacity of activated T and NK cells could be targeted to cancer cells by anchoring antibodies to their cell surface. Using metabolic glycoengineering to introduce azide moieties to the cellular surface, we covalently attached a dibenzocyclooctyne-modified antibody using the strain-promoted alkyne azide cycloaddition reaction, creating antibody-conjugated T and NK cells. We targeted the immune cells to tumors possessing the xenoantigen, N-glycolyl neuraminic acid GM3 ganglioside, using the 14F7hT antibody. These activated T and NK cells are “armed” with tumour-homing capabilities that specifically lyses antigen-positive cancer cells without off-target toxicities. Moreover, when exposed to target cells, 14F7hT-conjugated T cells that are not preactivated exhibit increased perforin, granzyme, CD69, and CD25 expression and specific cell killing.ConclusionsThis research shows the potential for a non-genetic method for redirecting cytotoxic immune cells as a feasible and effective approach for tumor-targeted cell immunotherapy.Graphical

Synthesis of new 1,2,3-triazole-linked pyrimidines by click reaction

A mild and efficient synthesis of 1,4-disubstituted 1,2,3-triazole linked pyrimidines is reported using click reactions. These compounds were prepared by the reaction of 4-propargyl substituted 5-iodo-6-methyl-2(methylthio) pyrimidine with aryl and benzyl azides via copper-catalyzed azide-alkyne cycloaddition reactions in the presence of sodium ascorbate, as a reducing agent. Furthermore, the synthesized compounds were screened against the two bacterial strains pseudomonas aeruginosa and saphylococcus aureus.

Reactivity Profiling for High-Yielding Ynamine-Tagged Oligonucleotide Click Chemistry Bioconjugations.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a key ligation tool used to prepare bioconjugates. Despite the widespread utility of CuAAC to produce discrete 1,4-triazole products, the requirement of a Cu catalyst can result in oxidative damage to these products. Ynamines are superior reactive groups in CuAAC reactions and require lower Cu loadings to produce 1,4-triazole products. This study discloses a strategy to identify optimal reaction conditions for the formation of oligodeoxyribonucleotide (ODN) bioconjugates. First, the surveying of reaction conditions identified that the ratio of Cu to the choice of reductant (i.e., either sodium ascorbate or glutathione) influences the reaction kinetics and the rate of degradation of bioconjugate products. Second, optimized conditions were used to prepare a variety of ODN-tagged products and ODN-protein conjugates and compared to conventional CuAAC and Cu-free azide-alkyne (3 + 2)cycloadditions (SPAAC), with ynamine-based examples being faster in all cases. The reaction optimization platform established in this study provides the basis for its wider utility to prepare CuAAC-based bioconjugates with lower Cu loadings while maintaining fast reaction kinetics.

‘Clickable’ polymer brush coated magnetic nanoparticles: Employing Diels-Alder and azide-alkyne cycloaddition for modular targeted drug delivery platforms

Effective methods of multi-functionalization of nanomaterials are essential for fabricating effective targeted drug delivery systems. Herein, we disclose the fabrication of polymer brush-coated magnetic nanoparticles that could be functionalized with drugs and targeting ligands through orthogonal click reactions. In particular, polymers containing electron-rich furan groups as functionalization handles are grown from the surface of magnetic nanoparticles using the ‘graft-from’ approach. Furthermore, azide groups are installed at the chain end of polymer brushes to furnish an orthogonally functionalizable system. The attachment of maleimide-containing fluorescent dyes and cytotoxic drugs using the Diels-Alder reaction is demonstrated. Drug-conjugated nanoparticles functionalized with integrin-targeting peptide using the azide-alkyne cycloaddition reaction undergo preferential uptake in cancer cells and show dose-dependent cytotoxicity. We envision that the modularly functionalizable system disclosed here could target various cancer cells using an appropriate combination of drugs and targeting groups.

Electron-withdrawing effect of polyoxometalates in Cu(I)-based metal–organic frameworks for enhanced azide-alkyne “click” reaction

Boosting the nucleophilicity of Cu(I) sites is an essential strategy to enhance the efficiency of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In this work, a Lindquist-type polyoxometalate (POM)-based metal–organic framework, [CuI4(W6O19)2(L)]·2H2O (NEAU-1), was synthesized via an in-situ solvothermal method. Single-crystal X-ray diffraction results reveal that NEAU-1 exhibits a sandwich structure, with POMs intercalated between the two-dimensional layers formed by resorcin[4]arene ligands and Cu(I) ions. NEAU-1 possesses abundant Cu(I) active sites and high chemical stability, making it an effective heterogeneous catalyst for the CuAAC reaction. More importantly, the presence of POMs effectively reduces the electron cloud density around Cu(I) sites, significantly lowering the energy barrier for the formation of copper-acetylide compounds and facilitating subsequent nucleophilic reactions. The synergistic catalytic effect of POMs and Cu(I) can achieve a conversion rate of over 99 % for benzyl azide and phenylacetylene within 40 min. This work presents a sustainable molecular-level strategy to enhance the activity of the CuAAC reaction.

Alkyne-rich patchy polymer colloids prepared by surfactant-free emulsion polymerization

While free radical polymerization methods are employed frequently to prepare sub-micron polymer particles, we hypothesized that surfactant-free emulsion polymerization (SFEP)1Surfactant-free emulsion polymerization1 methodology may prove beneficial for obtaining functional polymer particles by solution polymerization methods that preclude the need for conventional surfactants. To test the effectiveness of SFEP for the preparation of functional colloids, solution polymerization of several monomers, including propargyl acrylate (PA),2Propargyl acrylate.2 styrene (Sty)3Styrene.3 and tert-butyl acrylate (t-BA),4Tert-butyl acrylate.4 was performed over a range of monomer ratios and reaction scales. Electron microscopy and infrared spectroscopy were employed to evaluate the outcome of SFEP for particle size, shape, surface anisotropies, and chemical composition. Combining this characterization with optimized SFEP synthesis, we found that spherical polymer particles—homopolymers of PA as well as copolymers—were obtained in the 60–300 nm diameter size range. Successful inclusion of PA enabled the use of the particles in copper-catalyzed azide-alkyne cycloaddition reactions (CuAAc).5Copper-catalyzed azide-alkyne cycloaddition5 Moreover, electron microscopy characterization with backscattering revealed chemical and shape anisotropies on copolymer particles indicative of monomer phase-separation during particle formation. Overall, the SFEP methodology represents a straightforward, one-pot, bottom-up approach to yield a library of functional polymer particles, while avoiding undesirable aspects associated with conventional surfactants.

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies.

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, "clickable" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.

Repurposing Copper(II)/THPTA as A Bioorthogonal Catalyst for Thiazolidine Bond Cleavage.

Metal-mediated chemical transformations are promising approaches to manipulate and regulate proteins in fundamental biological research and therapeutic development. Nevertheless, unlike bond-forming reactions, the exploration of selective bond cleavage reactions catalyzed by metals that are fully compatible with proteins and living systems remains relatively limited. Here, it is reported that Copper(II)/tris(3-hydroxypropyltriazolylmethyl)amine (THPTA), commonly used in copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, can be repurposed as a new bioorthogonal catalyst for thiazolidine (Thz) bond cleavage. This process liberates an α-oxo-aldehyde group under physiological conditions, without requiring additional additives. To showcase the utility of this method, this simple catalyst system is coupled with genetic code expansion technology to achieve on-demand activation of genetically encoded Thz-caged α-oxo-aldehydes, enabling further functionalization of proteins. For the first time, this cell-compatible Thz uncaging reaction allows for the site-specific installation of α-oxo-aldehydes at the internal positions of proteins in phage and bacterial surface display systems, expanding the chemical space of proteins. Overall, this study expands the toolkit of bioorthogonal catalysts and paves the way for metal-promoted chemical reactions in living systems, potentially benefiting various applications in the future.

Oxidation-Controlled, Strain-Promoted Tellurophene-Alkyne Cycloaddition (OSTAC): A Bioorthogonal Tellurophene-Dependent Conjugation Reaction.

Tellurophene-bearing small molecules have emerged as valuable tools for localizing cellular activities in vivo using mass cytometry. To broaden the utility of tellurophenes in chemical biology, we have developed a bioorthogonal reaction to facilitate tagging of tellurophene-bearing conjugates for downstream applications. Using TePhe, a tellurophene-based phenylalanine analogue, labeled recombinant proteins were generated for reaction development. Using these proteins, we demonstrate an oxidation-controlled, strain-promoted tellurophene-alkyne cycloaddition (OSTAC) reaction. Mild oxidation of the tellurophene ring with N-chlorosuccinimide produces a reactive Te(IV) species which undergoes rapid (k > 100 M-1 s-1) cycloaddition with bicyclo[6.1.0]nonyne (BCN) yielding a benzo-fused cyclooctane. Selective labeling of TePhe-containing proteins can be achieved in complex protein mixtures and on fixed cells. OSTAC reactions can be combined with strain-promoted azide alkyne cycloaddition (SPAAC) and copper-catalyzed azide alkyne click (CuAAC) reactions. Demonstrating the versatility of this approach, we observe the expected staining patterns for 5-ethynyl-2'-deoxyuridine (DNA synthesis-CuAAC) and immunohistochemistry targets in combination with TePhe (protein synthesis-OSTAC) in fixed cells. The favorable properties of the OSTAC reaction suggest its broad applicability in chemical biology.

Conjugation of CRAMP18-35 Peptide to Chitosan and Hydroxypropyl Chitosan via Copper-Catalyzed Azide-Alkyne Cycloaddition and Investigation of Antibacterial Activity.

We developed a synthesis strategy involving a diazo transfer reaction and subsequent click reaction to conjugate a murine cathelicidin-related antimicrobial peptide (CRAMP18-35) to chitosan and hydroxypropyl chitosan (HPC), confirmed the structure, and investigated the antimicrobial activity. Chitosan azide and HPC-azide were prepared with a low degree of azidation by reacting the parent chitosan and HPC with imidazole sulfonyl azide hydrochloride. CRAMP18-35 carrying an N-terminal pentynoyl group was successfully grafted onto chitosan and HPC via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The chitosan-peptide conjugates were characterized by IR spectroscopy and proton NMR to confirm the conversion of the azide to 1,2,3-triazole and to determine the degree of substitution (DS). The DS of the chitosan and HPC CRAMP18-35 conjugates was 0.20 and 0.13, respectively. The antibacterial activity of chitosan-peptide conjugates was evaluated for activity against two species of Gram-positive bacteria, Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis), and two species of Gram-negative bacteria, Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). The antimicrobial peptide conjugates were selectively active against the Gram-negative bacteria and lacking activity against Gram-positive bacteria.

Click chemistry-mediated stable isotope labeling combined with HPLC-MS/MS analysis for highly sensitive determination of steroid hormones

Steroid hormone residues in food are a significant sources of endocrine disrupting chemicals (EDCs) that can adversely affect public health. However, the current analytical methods for determining steroid hormones using liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be challenging due to the poor ionization efficiency of steroid hormones and the matrix effect of complex food samples. Herein, based on Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and stable isotope labeling (SIL) technique, a novel pair of chemoselective probes ABI/d5-ABI was precisely designed and synthesized. This pair of probes comprises a H/D isotope tag, a linker, a reactive site azido group (N3) and a MS tag (imidazolium salt). The probe ABI was employed to label ethynyl-containing steroid hormones in real samples and d5-ABI was applied to label standards, respectively, followed by mixing the two labeled samples for high performance (HP)LC-MS/MS analysis. It was found that the ionization efficiencies of target analytes were increased by 17–4532 folds after ABI labeling. More importantly, the heavy labeled samples serving as internal standards (ISs) can effectively compensate matrix effect during HPLC-MS/MS analysis. Finally, the proposed SIL-HPLC-MS/MS method was successfully used to highly sensitive determine four synthetic steroid hormones in food samples (milk, pork and egg). Furthermore, the good detection limits (0.015–0.020 ng/mL), satisfactory recoveries (75.7–122.9 %), and precisions (RSDs less than 9.2 %) were obtained. Hence, the established method not only provides new insights in designing SIL probes for determination of ethynyl-containing analytes within complex matrix, but also extends the application of CuAAC reaction in the field of food chemistry.

Development of Alginate-Based Biodegradable Radioactive Microspheres Labeled with Positron Emitter through Click Chemistry Reaction: Stability and PET Imaging Study.

Biodegradable radioactive microspheres labeled with positron emitters hold significant promise for diagnostic and therapeutic applications in cancers and other diseases, including arthritis. The alginate-based polymeric microspheres offer advantages such as biocompatibility, biodegradability, and improved stability, making them suitable for clinical applications. In this study, we developed novel positron emission tomography (PET) microspheres using alginate biopolymer radiolabeled with gallium-68 (68Ga) through a straightforward conjugation reaction. Polyethylenimine (PEI)-decorated calcium alginate microspheres (PEI-CAMSs) were fabricated and further modified using azadibenzocyclooctyne-N-hydroxysuccinimide ester (ADIBO-NHS). Subsequently, azide-functionalized NOTA chelator (N3-NOTA) was labeled with [68Ga]Ga to obtain [68Ga]Ga-NOTA-N3, which was then reacted with the surface-modified PEI-CAMSs using strain-promoted alkyne-azide cycloaddition (SPAAC) reaction to develop [68Ga]Ga-NOTA-PEI-CAMSs, a novel PET microsphere. The radiolabeling efficiency and radiochemical stability of [68Ga]Ga-NOTA-PEI-CAMSs were determined using the radio-instant thin-layer chromatography-silica gel (radio-ITLC-SG) method. The in vivo PET images were also acquired to study the in vivo stability of the radiolabeled microspheres in normal mice. The radiolabeling efficiency of [68Ga]Ga-NOTA-PEI-CAMSs was over 99%, and the microspheres exhibited high stability (92%) in human blood serum. PET images demonstrated the stability and biodistribution of the microspheres in mice for up to 2 h post injection. This study highlights the potential of biodegradable PET microspheres for preoperative imaging and targeted radionuclide therapy. Overall, the straightforward synthesis method and efficient radiolabeling technique provide a promising platform for the development of theranostic microspheres using other radionuclides such as 90Y, 177Lu, 188Re, and 64Cu.

Cu58(SeC6H5)24(Dppe)6Se16]2+ assembled from tetrahedra and octahedra: synthesis, characterization, structure and catalytic properties.

Herein, we successfully synthesized a copper nanocluster, [Cu58(SeC6H5)24(Dppe)6Se16]2+. The Cu58 features a tetrahedral Cu4 core, surrounded by tetrahedral Se4 and octahedral Cu6 subunits, and further stabilized by Cu3Se3, Cu3(SeR)3, and DppeCu2 staples, which can be interpreted as an assembly of tetrahedral and octahedral units. Density functional theory (DFT) calculations were employed to investigate the electronic structure of Cu58. This nanocluster demonstrates excellent catalytic properties in copper-catalyzed [3+2] azide-alkyne cycloaddition (CuAAC) reactions. Additionally, Cu58 enriches the structural diversity of copper-based nanoclusters, providing valuable insights for future structural predictions.

Ag20 Nanoclusters with Surface Azides as an Easily Functionalized Platform for Diverse Chemical Applications.

Modifying atomically precise nanocluster surfaces while maintaining the cluster core remains a key challenge. Herein, the synthesis, structure, and properties of two targeted Ag20 nanoclusters (NCs) with eight surface azide moieties, [CO3@Ag20(StBu)10(m-N3-C6H4COO)8(DMF)4] (1-m) and [CO3@Ag20(StBu)10(p-N3-C6H4COO)8(DMF)4] (1-p) are reported, where DMF is N,N-dimethylformamide. These AgNCs are designed to undergo cluster surface strain-promoted azide-alkyne cycloaddition (CS-SPAAC) reactions, introducing new functionality to the cluster surface. Reactivity is screened using model strained cyclooctynes. Reaction products and parent clusters are characterized by UV-vis, FT-IR, and NMR spectroscopies. The structure of the parent clusters and presence of surface azides is confirmed by single crystal X-ray diffraction (SCXRD) analysis. Clusters 1-m and 1-p are found to be amenable to CS-SPAAC reactions with retention of the NC frameworks, opening new routes for efficient modification of AgNC for applications.

Decoration of GW9662 scaffold with a fragment-like hit via copper-catalyzed azide-alkyne cycloaddition reaction into peroxisome proliferator-activated receptor γ agonists

PPARγ is a member of nuclear receptor superfamily, which possesses a large Y-shaped cavity in the ligand-binding pocket. GW9662 is a well-known PPARγ antagonist which covalently reacts with the Cys285 residue via nucleophilic substitution. In contrast to its irreversibility, the ability of GW9662 to prevent other ligands from accessing the ligand-binding pocket is partly defective. By focusing on this incompleteness, we develop an integrated approach to create a new PPARγ agonist by using a structure of GW9662 as a scaffold for linking with a fragment compound. A screening of 1,040 compounds identified a partner ligand which synergistically activates PPARγ transcription in combination with GW9662. We introduced an azido or alkyne group to GW9662 or the identified fragment hit, respectively, and then connected the two structures via copper-catalyzed azide-alkyne cycloaddition. A coupling reaction provided a series of hybrid structure with triazole linker, among which the compounds with a bent configuration function as a partial PPARγ agonist. These results highlight a potential utility of GW9662 for the decoration with a fragment compound to develop a covalent agonist for PPARγ activation.

Hierarchical single-crystal-to-single-crystal transformations of a monomer to a 1D-polymer and then to a 2D-polymer

Designing and synthesizing flawless two-dimensional polymers (2D-Ps) via meticulous molecular preorganization presents an intriguing yet challenging frontier in research. We report here the single-crystal-to-single-crystal (SCSC) synthesis of a 2D-P via thermally induced topochemical azide-alkyne cycloaddition (TAAC) reaction. A designed monomer incorporating two azide and two alkyne units is synthesized. The azide and alkyne groups are preorganized in the monomer crystal in reactive geometries for polymerizations in two orthogonal directions. On heating, the polymerizations proceed in a hierarchical manner; at first, the monomer reacts regiospecifically in a SCSC fashion to form a 1,5-triazolyl-linked 1D polymer (1D-P), which upon further heating undergoes another SCSC polymerization to a 2D-P through a second regiospecific TAAC reaction forming 1,4-triazolyl-linkages. Two different linkages in orthogonal directions make this an architecturally attractive 2D-P, as determined, at atomic resolution, by single-crystal X-ray diffraction. The 2D-P reported here is thermally stable in view of the robust triazole-linkages and can be exfoliated as 2D-sheets.

Azidodifluoromethanide (N3CF2-): In Situ Generation and Nucleophilic Addition to Aldehydes.

A facile one-pot approach for the azidodifluoromethylation of aldehydes via in situ-generated azidodifluoromethenide (N3CF2-) utilizing commercially available TMSCF2Br and NaN3 is disclosed. The formed O-silyl ether products are obtained in yields of up to 91% in short reaction times at ambient temperature. Examples of both inter- and intramolecular [3 + 2] azide-alkyne cycloaddition reactions of the installed azidodifluoromethyl handles are also presented, demonstrating the prospective synthetic and biochemical functionality and utility.

Investigation of Huisgen's Noble metal catalyst click reaction mechanism for the synthesis of 1,4-disubstituted 1,2,3-triazoles

The current study delves into the mechanistic intricacies of azide-alkyne cycloaddition reactions (MAAC) catalyzed by transition metals (M = Cu, Ag, and Au) bound to N-heterocyclic carbene (NHC) ligands, utilizing Density Functional Theory (DFT) calculations at the MN12-L/Def2-SVP level of theory, with Def2-TZVP for metal atoms, to shed light on the 1,4-regioisomer formation. A detailed comparison between mono- and bi-nuclear catalytic pathways for these metal complexes is presented. Our findings underscore the nuanced role of the metal identity in dictating the reaction's course, with a notable preference for a stepwise mechanism across the board, except in the mononuclear pathway of Au and Ag, which follows a concerted mechanism. The activation energies, analyzed in toluene solvent, underscore the efficiency of the binuclear pathway for all metals, showcasing significantly lower activation barriers (18.76 kcal/mol for Au and Ag, and 8.47 kcal/mol for Cu) compared to the mononuclear route. This distinction highlights the potential for optimizing catalytic performance through careful selection of metal-NHC combinations, providing valuable insights for the design of efficient catalysts in click chemistry applications. The study not only reaffirms the superior efficacy of the binuclear pathway but also enriches our understanding of metal-catalyzed MAAC reactions, contributing to the advancement of catalysis science and offering avenues for the development of novel synthetic strategies in organic chemistry.

Indole–thiazolidinedione–triazole hybrids: synthesis, molecular docking, absorption, distribution, metabolism and excretion (ADME) profiling, and biological evaluation as α-amylase inhibitors

Abstract A novel series of hybrid indole–thiazolidinedione–triazole derivatives (6a-l) were synthesized and assessed for their in vitro inhibitory activity against porcine pancreatic α-amylase. The synthetic procedure consists of 3 steps. A crucial step in this process involves the generation of novel target molecules using a Cu(I)-catalyzed azide–alkyne cycloaddition reaction. The α-amylase inhibition IC50 value of the targeted compounds ranged from 0.51 ± 0.02 to 7.99 ± 0.28 μM as compared with 0.68 ± 0.02 μM with acarbose as the standard drug. Using the Autodock technique, all the derivatives 6a-l were subjected to molecular docking investigations against porcine pancreatic α-amylase (PDB ID: 1OSE). Moreover, it was discovered that the docked compounds had excellent binding affinities that ranged from −10.1 to −10.8 kcal/mol as compared with the standard −7.9 kcal/mol. Additionally, a comprehensive analysis of the physicochemical and pharmacokinetic properties associated with absorption, distribution, metabolism and excretion (ADME) was conducted for all the synthesized compounds.