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One-pot parallel synthesis of 1,3,5-trisubstituted 1,2,4-triazoles

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Abstract

An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible (“REAL”) compounds may be generated based on the proposed methodology. Analysis of physicochemical parameters shows that the library contains significant fractions of both drug-like and “beyond-rule-of-five” members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp3-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.

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Data availability

Library member characterization data not presented in the supplementary material are available from authors upon request. Compound library members generated in this study can be made available on request, but payment and/or a completed Materials Transfer Agreement shall be required if there is potential for commercial application. There are restrictions on the availability of the synthon lists with the reactivity features that have been used to generate the chemical space owing to commercial confidentiality reasons.

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Acknowledgements

The authors thank Dr. Angelika Konovets for the compound QC management, Mr. Bohdan V. Vashchenko and Ms. Vladyslava Prykhodko for their help with TOC graphics preparation, and Prof. Andrey A. Tolmachev for his encouragement and support.

Funding

The work was funded by Enamine Ltd. and NIH grant GM133836 (to Y.S.M.). O.O.G. was also funded by Ministry of Education and Science of Ukraine (grants No. 19BF037-03 and 21BF037-01 M).

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Authors and Affiliations

  1. Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094, Ukraine

    Dmytro S. Radchenko, Vasyl S. Naumchyk, Andrii A. Kyrylchuk & Oleksandr O. Grygorenko

  2. Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine

    Dmytro S. Radchenko, Kateryna E. Gubina, Yurii S. Moroz & Oleksandr O. Grygorenko

  3. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv, 02094, Ukraine

    Andrii A. Kyrylchuk

  4. Chemspace, Chervonotkatska Street 78, Kyiv, 02094, Ukraine

    Igor Dziuba & Yurii S. Moroz

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  1. Dmytro S. Radchenko
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  2. Vasyl S. Naumchyk
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  3. Igor Dziuba
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  4. Andrii A. Kyrylchuk
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  7. Oleksandr O. Grygorenko
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Contributions

OOG and DSR contributed to conceptualization; DSR and VSN provided methodology; DSR, ID, and VSN performed validation; OOG, AAK, and DSR performed formal analysis; DSR, VSN, ID, and KEG were involved in investigation; DSR, YSM, ID, and KEG contributed to data curation; OOG and AAK performed writing—original draft; OOG, DSR, and YSM performed writing—review & editing; AAK and OOG helped with visualization; OOG and DSR supervised the study; DSR and YSM were involved in project administration; YSM and OOG performed funding acquisition.

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Correspondence to Oleksandr O. Grygorenko.

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Radchenko, D.S., Naumchyk, V.S., Dziuba, I. et al. One-pot parallel synthesis of 1,3,5-trisubstituted 1,2,4-triazoles. Mol Divers 26, 993–1004 (2022). https://doi.org/10.1007/s11030-021-10218-2

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