Design, synthesis, and evaluation of the novel ozagrel-paeonol codrug with antiplatelet aggregation activities as a potent anti-stroke therapeutic agent

Chijing Zuo; Fulong Yan; Jie Wang; Yulong Zhu; Wenhui Luo; Yan Liu; Wanhui Liang; Weidong Yu; Jingwei Zhang; Daiyin Peng; Xiaodong Ma; Can Peng

doi:10.3389/fphar.2024.1362857

Design, synthesis, and evaluation of the novel ozagrel-paeonol codrug with antiplatelet aggregation activities as a potent anti-stroke therapeutic agent

Front Pharmacol. 2024 Mar 19:15:1362857. doi: 10.3389/fphar.2024.1362857. eCollection 2024.

Authors

Chijing Zuo^#¹, Fulong Yan^#¹, Jie Wang^#¹, Yulong Zhu¹, Wenhui Luo¹, Yan Liu¹, Wanhui Liang¹, Weidong Yu¹, Jingwei Zhang¹, Daiyin Peng^{1

2}, Xiaodong Ma¹, Can Peng^{1

2

3

4

5

6}

Affiliations

¹ School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
² MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, China.
³ Generic Technology Research Center for Anhui TCM Industry, Anhui University of Chinese Medicine, Hefei, China.
⁴ Rural Revitalization Collaborative Technical Service Center of Anhui Province, Anhui University of Chinese Medicine, Hefei, China.
⁵ Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Hefei, Anhui, China.
⁶ Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China.

^# Contributed equally.

Abstract

Introduction: Ischemic stroke is the second most common chronic disease worldwide and is associated with high morbidity and mortality. Thromboembolism and platelet aggregation are the most characteristic features of stroke. Other than aspirin, no standard, accepted, or effective treatment for acute ischemic stroke has been established. Consequently, it is essential to identify novel therapeutic compounds for this condition. Methods: In this study, novel ozagrel/paeonol-containing codrugs were synthesized and characterized using ¹H-NMR, ¹³C-NMR, and mass spectroscopy. Their antiplatelet aggregation activity was evaluated, with compound PNC₃ found to exhibit the best effect. Subsequently, studies were conducted to assess its neuroprotective effect, pharmacokinetic properties and model its binding mode to P2Y12 and TXA2, two proteins critical for platelet aggregation. Results: The results indicated that PNC3 has good bioavailability and exerts protective effects against oxygen-glucose deprivation injury in PC12 cells. Molecular docking analysis further demonstrated that the compound interacts with residues located in the active binding sites of the target proteins. Conclusion: The codrugs synthesized in this study display promising pharmacological activities and have the potential for development as an oral formulation.

Keywords: antiplatelet aggregation activity; molecular docking; neuroprotective effect; ozagrel; paeonol; pharmacokinetic properties.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by four grants from Research Funds of Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine of IHM, the Distinguished Young Scholars’ Science Project for Universities in Anhui province, the Major Special Science and Technology of Anhui Province, and Anhui Universities Collaborative Innovation Project (nos 2023CXMMTCM006, 2023AH020035, 202103a07020001, GXXT-2022-075, GXXT-2022-084, and GXXT-2020-025).