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Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions.

ABSTRACT: To identity fast-acting, multistage antimalarial agents, a series of pyridylvinylquinoline-triazole analogues have been synthesized via CuAAC. Most of the compounds display significant inhibitory effect on the drug-resistant malarial Dd2 strain at low submicromolar concentrations. Among the tested analogues, compound 60 is the most potent molecule with an EC₅₀ value of 0.04 ± 0.01 μM. Our current study indicates that compound 60 is a fast-acting antimalarial compound and it demonstrates stage specific action at the trophozoite phase in the P. falciparum asexual life cycle. In addition, compound 60 is active against both early and late stage P. falciparum gametocytes. From a mechanistic perspective, compound 60 shows good activity as an inhibitor of β-hematin formation. Collectively, our findings suggest that fast-acting agent 60 targets dual life stages of the malarial parasites and warrant further investigation of pyridylvinylquinoline hybrids as new antimalarials.

SUBMITTER: Huang G

PROVIDER: S-EPMC7744367 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Green Methodologies for Copper(I)-Catalyzed Azide-Alkyne Cycloadditions: A Comparative Study.

Project description:Successful copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions may be achieved by several methods. In this paper, four synthetic protocols were performed for direct comparison of time required for the synthesis, yield, and purity of the 1H-1,2,3-triazole products. The methods with Cu(I) catalysts were conventional, microwave heating, solvent-free, and a method using glycerol solvent. The compounds synthesized in this paper were known non-fluorinated triazoles and new fluorinated triazoles. The results lead to the conclusion that the microwave method should be strongly considered for CuAAC syntheses.

| S-EPMC6429464 | biostudies-literature

Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions.

Project description:Copper(I)-catalyzed azide-alkyne cycloaddition has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat-flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the carbon-nitrogen bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.

| S-EPMC3651910 | biostudies-literature

Electrochemically protected copper(I)-catalyzed azide-alkyne cycloaddition.

Project description:The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has found broad application in myriad fields. For the most demanding applications that require high yields at low substrate concentrations, highly active but air-sensitive copper complexes must be used. We describe here the use of an electrochemical potential to maintain catalysts in the active Cu(I) oxidation state in the presence of air. This simple procedure efficiently achieves excellent yields of CuAAC products from both small-molecule and protein substrates without the use of potentially damaging chemical reducing agents. A new water-soluble carboxylated version of the popular tris(benzyltriazolylmethyl)amine (TBTA) ligand is also described. Cyclic voltammetry revealed reversible or quasi-reversible electrochemical redox behavior of copper complexes of the TBTA derivative (2; E(1/2)=60 mV vs. Ag/AgCl), sulfonated bathophenanthroline (3; E(1/2)=-60 mV), and sulfonated tris(benzimidazoylmethyl)amine (4; E(1/2) approximately -70 mV), and showed catalytic turnover to be rapid relative to the voltammetry time scale. Under the influence of a -200 mV potential that was established by using a reticulated vitreous carbon working electrode, CuSO4 and 3 formed a superior catalyst. Electrochemically protected bioconjugations in air were performed by using bacteriophage Qbeta that was derivatized with azide moieties at surface lysine residues. Complete derivatization of more than 600 reactive sites per particle was demonstrated within 12 h of electrolysis with substoichiometric quantities of Cu3.

| S-EPMC3574790 | biostudies-literature

Double Nitroxide Labeling by Copper-Catalyzed Azide-Alkyne Cycloadditions with Noncanonical Amino Acids for Electron Paramagnetic Resonance Spectroscopy.

Project description:Electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling (SDSL) is an important tool to obtain long-range distance restraints for protein structural research. We here study a variety of azide- and alkyne-bearing noncanonical amino acids (ncAA) in terms of protein single- and double-incorporation efficiency via nonsense suppression, metabolic stability, yields of nitroxide labeling via copper-catalyzed [3 + 2] azide-alkyne cycloadditions (CuAAC), and spectroscopic properties in continuous-wave and double electron-electron resonance measurements. We identify para-ethynyl-l-phenylalanine and para-propargyloxy-l-phenylalanine as suitable ncAA for CuAAC-based SDSL that will complement current SDSL approaches, particularly in cases in which essential cysteines of a target protein prevent the use of sulfhydryl-reactive spin labels.

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Investigation of copper-free alkyne/azide 1,3-dipolar cycloadditions using microwave irradiation.

Project description:The prevalence of 1,3-dipolar cycloadditions of azides and alkynes within both biology and chemistry highlights the utility of these reactions. However, the use of a copper catalyst can be prohibitive to some applications. Consequently, we have optimized a copper-free microwave-assisted reaction to alleviate the necessity for the copper catalyst. A small array of triazoles was prepared to examine the scope of this approach, and the methodology was translated to a protein context through the use of unnatural amino acids to demonstrate one of the first microwave-mediated bioconjugations involving a full length protein.

| S-EPMC5761740 | biostudies-literature

Conditional Copper-Catalyzed Azide-Alkyne Cycloaddition by Catalyst Encapsulation.

Project description:Supramolecular encapsulation is known to alter chemical properties of guest molecules. We have applied this strategy of molecular encapsulation to temporally control the catalytic activity of a stable copper(I)-carbene catalyst. Encapsulation of the copper(I)-carbene catalyst by the supramolecular host cucurbit[7]uril (CB[7]) resulted in the complete inactivation of a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The addition of a chemical signal achieved the near instantaneous activation of the catalyst, by releasing the catalyst from the inhibited CB[7] catalyst complex. To broaden the scope of our on-demand CuAAC reaction, we demonstrated the protein labeling of vinculin with the copper(I)-carbene catalyst, to inhibit its activity by encapsulation with CB[7] and to initiate labeling at any moment by adding a specific signal molecule. Ultimately, this strategy allows for temporal control over copper-catalyzed click chemistry, on small molecules as well as protein targets.

| S-EPMC7318279 | biostudies-literature

Relative performance of alkynes in copper-catalyzed azide-alkyne cycloaddition.

Project description:Copper-catalyzed azide-alkyne cycloaddition (CuAAC) has found numerous applications in a variety of fields. We report here only modest differences in the reactivity of various classes of terminal alkynes under typical bioconjugative and preparative organic conditions. Propargyl compounds represent an excellent combination of azide reactivity, ease of installation, and cost. Electronically activated propiolamides are slightly more reactive, at the expense of increased propensity for Michael addition. Certain alkynes, including tertiary propargyl carbamates, are not suitable for bioconjugation due to copper-induced fragmentation. A fluorogenic probe based on such reactivity is available in one step from rhodamine 110 and can be useful for optimization of CuAAC conditions.

| S-EPMC4170714 | biostudies-literature

Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

Project description:The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle. Designing a chiral catalyst is further complicated by the complex mechanism of CuAAC. We report an enantioselective CuAAC (E-CuAAC), enabled by dynamic kinetic resolution (DKR). The E-CuAAC is high yielding and affords up to 99:1 er. The E-CuAAC can directly generate α-chiral triazoles in a complex molecular environment.

| S-EPMC6594181 | biostudies-literature

Solvent-free copper-catalyzed azide-alkyne cycloaddition under mechanochemical activation.

Project description:The ball-mill-based mechanochemical activation of metallic copper powder facilitates solvent-free alkyne-azide click reactions (CuAAC). All parameters that affect reaction rate (i.e., milling time, revolutions/min, size and milling ball number) have been optimized. This new, efficient, facile and eco-friendly procedure has been tested on a number of different substrates and in all cases afforded the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in high yields and purities. The final compounds were isolated in almost quantitative overall yields after simple filtration, making this procedure facile and rapid. The optimized CuAAC protocol was efficiently applied even with bulky functionalized ?-cyclodextrins (?-CD) and scaled-up to 10 g of isolated product.

| S-EPMC6272186 | biostudies-other

Photoinitiated Copper(I) Catalyzed Azide-Alkyne Cycloaddition Reaction for Ion Conductive Networks.

Project description:The photoinitiated copper(I) catalyzed azide-alkyne cycloaddition (photo-CuAAC) is a 'click' reaction that enables spatially and temporally controlled polymerizations. The solvent-less photopolymerization of multi-functional azide and cationic alkyne monomers results in the rapid formation of a charged polymer network. Full conversion of these monomers is achieved within 30 minutes under mild, blue-light irradiation conditions (470 nm light at 30 mW/cm2). The modulus of the material is readily tuned by controlling the ratio of di- and tri-functional alkyne monomers. Facile exchange of the hydrophobic bistriflimide counterion for a hydroxide anion yields an ion conductive polymer network with photopatternable charged regions. The spatiotemporal nature of the ionic photo-CuAAC reaction coupled with the chemical stability and mechanical flexibility suggests this chemistry is a facile and novel approach for ion-containing material synthesis (e.g., alkaline fuel cells components).

| S-EPMC7451218 | biostudies-literature

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