Tetrahedron Letters

Shuchun Zhao, Jing Wang, Zao Wang, Jianzong Li, Ling Zhang, Xiao Hu, Xiaodong Zhang, Jun Tang, Jingshun Zhang, Shuyu Li, Shengtao Yang, Xinqiang Gao, Yuanqing Tang

Tetrahedron Letters,Volume 129,2023,154719,ISSN 0040-4039.

https://doi.org/10.1016/j.tetlet.2023.154719

Abstract

This article presents the synthetic methods of double-bonded azacycles and their applications as bioisosteres in drug discovery. Our focus was on the creation of fragment (2) (1,1′,4,4′-tetrahydro-2H,2′H-3,3′-biazetylidene) and its utilization as a bioisostere in compound (34). The analysis of how FT-4202 (etavopivat), a new activator of the pyruvate kinase, and compound (34) bind with the PKR protein showed comparable interactions with the adjacent amino acids. Through biochemical and cellular evaluations, it was also demonstrated that the activities of compound (34) and its analogs align well with FT-4202. This finding points to the promising prospect of utilizing fragment (2) as a bioisostere for fragment (1).