Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists

A series of novel dual A(2A)/A(2B) AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A(2A) AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition,...

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Autores principales: Li, Zhi, Kou, Lijuan, Fu, Xinzhen, Xie, Zeping, Xu, Maolei, Guo, Lin, Lin, Tiantian, Gong, Shizhou, Zhang, Shumin, Liu, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Research Papers
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154793/
https://www.ncbi.nlm.nih.gov/pubmed/35616298
http://dx.doi.org/10.1080/14756366.2022.2077731
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author Li, Zhi
Kou, Lijuan
Fu, Xinzhen
Xie, Zeping
Xu, Maolei
Guo, Lin
Lin, Tiantian
Gong, Shizhou
Zhang, Shumin
Liu, Ming
author_facet Li, Zhi
Kou, Lijuan
Fu, Xinzhen
Xie, Zeping
Xu, Maolei
Guo, Lin
Lin, Tiantian
Gong, Shizhou
Zhang, Shumin
Liu, Ming
author_sort Li, Zhi
collection PubMed
description A series of novel dual A(2A)/A(2B) AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A(2A) AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A(2B) AR (IC(50) 14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A(2A)/A(2B) AR antagonists for cancer immunotherapy.
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spelling pubmed-91547932022-06-01 Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists Li, Zhi Kou, Lijuan Fu, Xinzhen Xie, Zeping Xu, Maolei Guo, Lin Lin, Tiantian Gong, Shizhou Zhang, Shumin Liu, Ming J Enzyme Inhib Med Chem Research Papers A series of novel dual A(2A)/A(2B) AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A(2A) AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A(2B) AR (IC(50) 14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A(2A)/A(2B) AR antagonists for cancer immunotherapy. Taylor & Francis 2022-05-26 /pmc/articles/PMC9154793/ /pubmed/35616298 http://dx.doi.org/10.1080/14756366.2022.2077731 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Papers
Li, Zhi
Kou, Lijuan
Fu, Xinzhen
Xie, Zeping
Xu, Maolei
Guo, Lin
Lin, Tiantian
Gong, Shizhou
Zhang, Shumin
Liu, Ming
Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title_full Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title_fullStr Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title_full_unstemmed Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title_short Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A(2A)/A(2B) adenosine receptor antagonists
title_sort design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual a(2a)/a(2b) adenosine receptor antagonists
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154793/
https://www.ncbi.nlm.nih.gov/pubmed/35616298
http://dx.doi.org/10.1080/14756366.2022.2077731
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