Recent applications of click chemistry in drug discovery

Jiang, Xiangyi; Hao, Xia; Jing, Lanlan; Wu, Gaochan; Kang, Dongwei; Liu, Xinyong; Zhan, Peng

doi:10.1080/17460441.2019.1614910

Cited by 162 publications

(100 citation statements)

References 48 publications

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“…[18] It should be noted that click chemistry approach was used not only as an instrument for conjugation of different portions of molecule but also for possible increase in biological activity due to introduction of 1,2,3-triazole fragment, which is a well-known pharmacophore. [19,20] Research strategy implied not only to prepare hybrid heterocyclic molecules but also to assess the effect of the nature and length of linker between camphor and cytisine fragments on their biological activity. To accomplish [2 + 3] cycloaddition reaction, we synthesized azide and acetylene building blocks.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

Аrtyushin

Moiseeva

Zarubaev

et al. 2019

Chemistry & Biodiversity

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A series of camphecene and quinolizidine alkaloid (−)‐cytisine conjugates has been obtained for the first time using ‘click’ chemistry methodology. The cytotoxicity and virus‐inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC50), 50 % inhibition dose (IC50) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1R,5S)‐3‐(6‐{4‐[(2‐{(E)‐[(1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐ylidene]amino}ethoxy)methyl]‐1H‐1,2,3‐triazol‐1‐yl}hexyl)‐1,2,3,4,5,6‐hexahydro‐8H‐1,5‐methanopyrido[1,2‐a][1,5]diazocin‐8‐one), which contains cytisine fragment separated from triazole ring by –C6H12– aliphatic linker, showed the highest activity at relatively low toxicity (CC50=168 μmol, IC50=8 μmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

Аrtyushin

Moiseeva

Zarubaev

et al. 2019

Chemistry & Biodiversity

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“…The CuAAC of organic azides and terminal alkynes is considered to be a versatile and promising approach to prepare new bioactive compounds, pharmaceutical lead compounds, bio-probes, soft materials among others [45][46][47][48][49][50].…”

Section: Cuaac Of Azidoethyl-nitroindazoles With Terminal Alkynesmentioning

confidence: 99%

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions

et al. 2019

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The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide-alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields.Molecules 2020, 25, 126 2 of 18 antipyretic, antioxidant, antiparasitic, antimicrobial, antitumoral and anti-inflammatory activities, among others [5][6][7][21][22][23].Indazoles are another important group of N-heterocycles with significant biological activities as nitric oxide synthase (NOS) inhibitors, kinase inhibitors, anti-inflammatory, anticancer, antimicrobial, antifungal, antimalarial, and antileishmanial agents, among others.Some anticancer and anti-inflammatory drugs based in indazole scaffolds are commercially available [24][25][26][27][28][29][30]. Besides the biological properties presented by indazole derivatives, this family of N-heterocycles also showed potential to be used in other fields as corrosion inhibitors, components for OLEDs and battery applications, and as copolymerizing molecules for new materials [31][32][33][34].Following our interest on developing synthetic approaches to functionalize the indazole core [35,36], we decided to follow the 1,3-dipolar cycloaddition methodology to substitute nitroindazoles with triazole or pyrazoline moieties, aiming in such way to obtain new compounds with improved biological features for different applications. In the strategy envisaged it was considered that the alkylation of indazole with 1,2-dibromoethane using liquid-liquid phase transfer catalysis, could afford not only the N-1and N-2-bromoethylindazoles, but also the corresponding N-1and N-2-vinylindazoles [37]. The annular tautomerisation of two nitrogen atoms (N-1, N-2) present in the indazole ring, has been explored in synthetic and theoretical studies concerning the substitution of N-H-indazole [38]. More recently, it was reported by our group that the reactivity of N-1 and N-2 alkylated indazole isomers is strongly dependent on the reaction conditions, namely, solvent proticity and pH, as well as, electronic and steric effects [39,40].Herein it is described the synthesis of a series of N-bromoethyl-nitroindazoles and N-vinyl-nitroindazoles reacting the corresponding nitroindazoles with 1,2-dibromoethane. A detailed analysis of the reaction conditions allowed to develop a simple, fast and inexpensive protocol to obtain both the vinyl and the bromoethyl derivatives in just one step in reasonable amounts. One of the bromoethyl derivatives was used to afford the corresponding azide, and its reactivity in CuAAC reactions with different...

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“…This trend is epitomized by the influence that 1,3-dipolar cycloaddition reactions have had on click chemistry, and most notably the azide-alkyne fusion reaction recognized [10] by Professor Rolf Huisgen. [11,12] Arguably, Huisgens early work on cycloaddi-tion chemistry has influenced the evolution of click chemistry more than any other; ultimately leading to the discovery of three high-profile breakthroughs: i) target accelerated in situ click chemistry as a tool for drug discovery; [13][14][15][16][17] ii) the regioselective stepwise copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC) reaction [18,19] -a transformation with an unrivaled breadth of application; [3,[20][21][22] and iii) the strain-promoted Huisgen 1,3-dipolar cycloaddition reaction between azide-alkyne (SPAAC, 2004), [23,24] used ubiquitously in bioconjugation applications (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Smedley

Barrow

et al. 2020

Angew Chem Int Ed

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Diversity Oriented Clicking (DOC) is a unified click‐approach for the modular synthesis of lead‐like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving “diversity with ease”, by combining classic C−C π‐bond click chemistry with recent developments in connective SuFEx‐technologies. We showcase 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click‐cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click‐library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3‐ and 1,5‐dipoles; while reaction with cyclic dienes yields several three‐dimensional bicyclic Diels–Alder adducts. Growing the library to 278 discrete compounds through late‐stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well‐plates—demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

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Recent applications of click chemistry in drug discovery

Cited by 162 publications

References 48 publications

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

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