Design, Synthesis, and Biological Activity Studies of Istradefylline Derivatives Based on Adenine as A2A Receptor Antagonists

Yiyun Wang; Haojie Xu; Hongyi Wang; Zhonghui Zheng; Zihui Meng; Zhibin Xu; Jiarong Li; Min Xue

doi:10.1021/acsomega.0c05741

Design, Synthesis, and Biological Activity Studies of Istradefylline Derivatives Based on Adenine as A_2A Receptor Antagonists

ACS Omega. 2021 Feb 4;6(6):4386-4394. doi: 10.1021/acsomega.0c05741. eCollection 2021 Feb 16.

Authors

Yiyun Wang^{1

2}, Haojie Xu^{1

2}, Hongyi Wang², Zhonghui Zheng², Zihui Meng¹, Zhibin Xu¹, Jiarong Li¹, Min Xue¹

Affiliations

¹ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Courtyard 8, Liangxiang Campus, Fangshan District, 102488 Beijing, P. R. China.
² Shandong Xinhua Pharmaceutical Co., Ltd., No. 1 Lutai Avenue, 255086 Zibo, Shandong, P. R. China.

Abstract

Due to its double bond, istradefylline rapidly isomerizes to Z-istradefylline when exposed to normal daylight in dilute solution. To solve the poor photostability of the istradefylline solution, a series of istradefylline derivatives (in total 17 compounds, including II-1 and II-2 series) were designed and synthesized, and their biological activity in inhibiting cAMP was evaluated. The IC₅₀ values of compounds II-1-3, II-2-1, II-2-2, II-2-3, II-2-4, and II-2-6 were 7.71, 6.52, 6.16, 7.23, 7.96, and 9.68 μg/mL, respectively, which had the same order of activity as that of istradefylline (IC₅₀ value was 1.94 μg/mL). The preliminary structure-activity relationship suggested that the 6-amino in adenine played an important role in binding an A_2A receptor. The results of photostability experiments showed that the photostability of the target compounds of II-1 and II-2 series was improved when compared with that of istradefylline.