The 1,2,3-triazole ring as a bioisostere in medicinal chemistry

Bonandi, Elisa; Christodoulou, Michael S.; Fumagalli, Gaia; Perdicchia, Dario; Rastelli, Giulio; Passarella, Daniele

doi:10.1016/j.drudis.2017.05.014

Cited by 550 publications

(348 citation statements)

References 95 publications

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“…The distance across the amide substituents increases by ≈1.2 Å in the triazole derivative, and the angle of orientation between the amide substituents is increased by ≈18.1° in the triazole. While these structural changes can be tolerated in many instances without negative consequences on biological activity and/or physiochemical properties, this did not prove to be the case in the VX‐809 and VX‐770 chemical series.…”

Section: Discussionmentioning

confidence: 98%

“…Since the development of efficient synthetic methodologies to prepare 1,2,3‐triazoles in the early 2000s, the use of the 1,2,3‐triazole as an amide bioisostere has proven to be a widely successful strategy in medicinal chemistry . As shown in Figure , the basis of the effective bioisosteric relationship is due to the similar topological and electronic characteristics of the 1,4‐disubstituted 1,2,3‐triazole and the trans ‐amide.…”

Section: Introductionmentioning

confidence: 99%

“…Impressively, numerous successful applications of the 1,2,3‐triazole as an amide bioisostere have been reported as recently reviewed by Passarella and coauthors . These examples span diverse therapeutic contexts including antiviral agents, chemotherapeutics, antibiofilm agents, antinociceptives, and antipsychotics .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

Doiron

Ody

et al. 2019

Chemistry A European J

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The 1,2,3‐triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX‐809 and VX‐770, prominent amide‐containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX‐809, displayed markedly reduced efficacy in F508del‐CFTR correction in cellular TECC assays in comparison to VX‐809. Surprisingly, triazole analogues derived from potentiator VX‐770 displayed no potentiation of F508del, G551D, or WT‐CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT‐CFTR similarly to VX‐770. The efficacy of 60 in the cell‐free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX‐770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3‐triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3‐triazole as an amide bioisostere.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

Doiron

Ody

et al. 2019

Chemistry A European J

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“…Since its discovery by Huisgen, the 1,3‐dipolar cycloaddition reaction between azide and alkyne has been applied for the syntheses of 1,4‐ and 1,5‐disubstituted‐1,2,3‐triazoles, which in turn have been served as important and key structural motifs in several applications ranging from biology to material sciences . However, the Huisgen reaction was characterized by being carried out at high temperatures, with a low rate and providing a mixture of both 1,4‐ and 1,5‐disubstituted‐1,2,3‐triazoles as regioisomers .…”

Section: Introductionmentioning

confidence: 99%

Polyvinylpolypyrrolidone‐Stabilized Copper Nanoparticles as an Efficient and Recyclable Heterogeneous Catalyst for the Click of 1,2,3‐Triazoles in Water

Bahsis

Himri

Ayouchia

et al. 2019

Macro Chemistry & Physics

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A simple, efficient, inexpensive, and friendly benign route for the preparation of highly stable monodisperse copper nanoparticles with an average of 4–5 nm is developed by using polyvinylpolypyrrolidone (PVPP) as a stabilizer. Chemical reaction of PVPP and copper(II) sulfate followed by the thermal chemical reduction of embedded copper(II) ions with ascorbic acid afford copper nanoparticles‐polyvinylpolypyrrolidone (CuNPs‐PVPP) nanocatalyst, which is systematically characterized by FT‐IR, Raman, transmission electron microscopy, X‐ray powder diffraction, scanning electron microscopy, dispersive X‐ray spectroscopy, and atomic absorption spectroscopy. The CuNPs‐PVPP system efficiently catalyzes the click chemistry reaction of azides–alkynes as well as one‐pot three‐component reactions to regioselectively produce the 1,4‐disubstituted‐1,2,3‐triazole isomer in excellent yields in water under mild reaction conditions. CuNPs‐PVPP is successfully recycled up to five times without significant loss of its catalytic efficiency and selectivity. Moreover, a mechanistic study is performed through density functional theory type calculations in order to explain the observed selectivity of CuNPs catalyst in copper(I)‐catalyzed azide–alkyne cycloaddition reactions. The cheap, simple work‐up, recoverability/reusability, and negligible residual traces in the final product (0.5 ppm) of this novel nanocatalyst are the significant features of this eco‐friendly green protocol.

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“…In addition, introduction of a 1,2,3‐triazole five‐ring system might improve the stability in liver microsomes. Also, different substituents were introduced into the 1‐position of the 1,2,3‐triazole to investigate structure–activity relationships (Figure ) …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors

Zhang

Zhao

et al. 2018

ChemMedChem

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BRD4 has been identified as a potential target for blocking proliferation in a variety of cancer cell lines. In this study, 3,5-dimethylisoxazole derivatives were designed and synthesized with excellent stability in liver microsomes as potent BRD4 inhibitors, and were evaluated for their BRD4 inhibitory activities in vitro. Gratifyingly, compound 11 h [3-((1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-4-phenyl-3,4-dihydroquinazolin-2(1H)-one] exhibited robust potency for BRD4(1) and BRD4(2) inhibition with IC values of 27.0 and 180 nm, respectively. Docking studies were performed to illustrate the strategy of modification and analyze the conformation in detail. Furthermore, compound 11 h was found to potently inhibit cell proliferation in the BRD4-sensitive cell lines HL-60 and MV4-11, with IC values of 0.120 and 0.09 μm, respectively. Compound 11 h was further demonstrated to downregulate c-Myc levels in HL-60 cells. In summary, these results suggest that compound 11 h is most likely a potential BRD4 inhibitor and is a lead compound for further investigations.

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The 1,2,3-triazole ring as a bioisostere in medicinal chemistry

Cited by 550 publications

References 95 publications

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

Polyvinylpolypyrrolidone‐Stabilized Copper Nanoparticles as an Efficient and Recyclable Heterogeneous Catalyst for the Click of 1,2,3‐Triazoles in Water

Design, Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors

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