Citation: Xiao Li, Manjiong Wang, Yunpeng Guo, Luoyifan Zhou, Yue Yao, Xiaobo Guo, Conglong Xia, Hanfang Liu, Zihan Wang, Tiankuo Zhang, Chao Zhang, Yi Ge, Xiaokang Li, Jian Li, Yixiang Xu. Discovery of novel psoralen derivatives as potent anti-heart failure agents through drug repurposing and secondary development[J]. Chinese Chemical Letters, ;2026, 37(11): 112287. doi: 10.1016/j.cclet.2025.112287 shu

Discovery of novel psoralen derivatives as potent anti-heart failure agents through drug repurposing and secondary development

Xiao Li ^{a, 1} ,
Manjiong Wang ^{a, 1} ,
Yunpeng Guo ^{a, 1} ,
Luoyifan Zhou ^a ,
Yue Yao ^a ,
Xiaobo Guo ^a ,
Conglong Xia ^b ,
Hanfang Liu ^a ,
Zihan Wang ^a ,
Tiankuo Zhang ^a ,
Chao Zhang ^a ,
Yi Ge ^e ,
Xiaokang Li ^{a, *,} ,
Jian Li ^{a, c, d, *,} ,
Yixiang Xu ^{a, *,}

a.
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b.
College of Pharmacy, Dali University, Dali 671000, China
c.
Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
d.
Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China
e.
School of Chemical Engineering, Shandong Chemical Engineering & Vocational College, Weifang 261000, China

xkli@ecust.edu.cn

jianli@ecust.edu.cn

yixxu@ecust.edu.cn

Received Date: 26 September 2025
Revised Date: 12 December 2025
Accepted Date: 15 December 2025
Available Online: 15 December 2025

Figures(6)

Heart failure (HF) constitutes a global health burden with elevated mortality and rehospitalization, underscoring the urgent need for novel therapeutics to improve outcomes. Herein, we reported the discovery of a psoralen analog, xanthotoxin (XAT), which is a natural product isolated from Synotis nagensium with cardioprotective effects. To overcome XAT's phototoxicity and poor aqueous solubility, the rational structural optimization was performed to yield 26 psoralen derivatives. Among them, A22 emerged as the optimal derivative, showing abolished phototoxicity, improved aqueous solubility, and potent efficacy at 5 mg/kg in both isoproterenol (ISO)-induced and myocardial infarction (MI)-induced HF models. Mechanistic studies demonstrated that A22 attenuated oxidative stress and cardiomyocyte apoptosis via activation of the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway. Favorable safety and pharmacokinetic profiles further supported its translational potential. Together, these data supported A22 as a promising candidate for HF therapy and justified continued preclinical investigation toward clinical development.
- Heart failure,
- Xanthotoxin,
- Phototoxicity,
- Structural optimization,
- Oxidative stress
1. [1]
  P.M. Becher, L.H. Lund, A.J.S. Coats, et al., Eur. Heart J. 43 (2022) 3005–3007. doi: 10.1093/eurheartj/ehac248
2. [2]
  S.J. Greene, J. Bauersachs, J.J. Brugts, et al., J. Am. Coll. Cardiol. 81 (2023) 413–424.
3. [3]
  G. Savarese, F. Lindberg, R.M. Christodorescu, et al., Eur. J. Heart Fail. 26 (2024) 1408–1418. doi: 10.1002/ejhf.3214
4. [4]
  Y. Wang, P. Tang, W. Tu, et al., Chin. Chem. Lett. 36 (2025) 109955. doi: 10.1016/j.cclet.2024.109955
5. [5]
  C.Y. Zhang, Y.L. Li, Z.J. Chu, et al., Chin. Chem. Lett. 35 (2024) 108206. doi: 10.1016/j.cclet.2023.108206
6. [6]
  P.J. Hauptman, R.A. Kelly, Circulation 99 (1999) 1265–1270. doi: 10.1161/01.CIR.99.9.1265
7. [7]
  M. Isaji, Curr. Opin. Investig. Drugs 8 (2007) 285–292.
8. [8]
  B. Zinman, C. Wanner, J.M. Lachin, et al., N. Engl. J. Med. 373 (2015) 2117–2128. doi: 10.1056/NEJMoa1504720
9. [9]
  M. Wang, X. Guo, H. Liu, et al., Acta Pharm. Sin. B 15 (2025) 3338–3342. doi: 10.3390/foods14193338
10. [10]
  Y. Liu, Chin. J. Ethnomed. Ethnopharm. 29 (2020) 119.
11. [11]
  J.A. Parrish, T.B. Fitzpatrick, L. Tanenbaum, et al., N. Engl. J. Med. 291 (1974) 1207–1211. doi: 10.1056/NEJM197412052912301
12. [12]
  G.W. Cox, C.G. Orosz, M.G. Lewis, et al., Int. J. Immunopharmacol. 10 (1988) 773–781. doi: 10.1016/0192-0561(88)90031-8
13. [13]
  H. Yang, J. Xiong, W. Luo, et al., Cell. Physiol. Biochem. 37 (2015) 361–374. doi: 10.1159/000430360
14. [14]
  A.B. Santamaria, D.W. Davis, D.X. Nghiem, et al., Cell Death Differ. 9 (2002) 549–560. doi: 10.1038/sj.cdd.4401007
15. [15]
  A. Wu, J. Lu, G. Zhong, et al., Phytother. Res. 36 (2022) 3805–3832. doi: 10.1002/ptr.7577
16. [16]
  J. Diekmann, I. Theves, K.A. Thom, et al., Molecules 25 (2020) 5242. doi: 10.3390/molecules25225242
17. [17]
  N. Kitamura, S. Kohtani, R. Nakagaki, J. Photochem. Photobiol. C: Photochem. Rev. 6 (2005) 168–185. doi: 10.1016/j.jphotochemrev.2005.08.002
18. [18]
  L. Mantry, R. Maayuri, V. Kumar, et al., Beilstein J. Org. Chem. 17 (2021) 2209–2259. doi: 10.3762/bjoc.17.143
19. [19]
  D.N. Primer, G.A. Molander, J. Am. Chem. Soc. 139 (2017) 9847–9850. doi: 10.1021/jacs.7b06288
20. [20]
  Y. Xu, C. Zhang, K. Jiang, et al., Acta Pharm. Sin. B 13 (2023) 1671–1685. doi: 10.1016/j.apsb.2022.08.023
21. [21]
  X. Li, Y. Yao, L. Zhou, et al., Acta Materia Medica 3 (2024) 133–146.
22. [22]
  P.W. Kenny, J. Med. Chem. 65 (2022) 14261–14275. doi: 10.1021/acs.jmedchem.2c01147
23. [23]
  J.N. Chythra, S.S. Mallajosyula, J. Chem. Inf. Model. 63 (2023) 208–223. doi: 10.1021/acs.jcim.2c01286
24. [24]
  L.Y. Fong, H.Y.D. Cheow, C.T. Ng, et al., Eur. J. Med. Chem. 296 (2025) 117833. doi: 10.1016/j.ejmech.2025.117833
25. [25]
  OECD Guideline For the Testing of Chemicals No. 432, Paris, 2024.
26. [26]
  M. Ceridono, P. Tellner, D. Bauer, et al., Regul. Toxicol. Pharmacol. 63 (2012) 480–488. doi: 10.1016/j.yrtph.2012.06.001
27. [27]
  H. Spielmann, M. Balls, J. Dupuis, et al., Toxicol. In Vitro 12 (1998) 305–327.
28. [28]
  Z. Chu, Y. Zhang, Y. Zhang, et al., J. Nanobiotechnology 23 (2025) 141. doi: 10.1186/s12951-025-03244-x
29. [29]
  H. Tsutsui, S. Kinugawa, S. Matsushima, Am. J. Physiol. Heart Circ. Physiol. 301 (2011) H2181–H2190. doi: 10.1152/ajpheart.00554.2011
30. [30]
  A. Qawasmeh, M. Qaisiya, A. Ishnaiwer, et al., Front. Nat. Prod. 4 (2025) 1593684. doi: 10.3389/fntpr.2025.1593684
31. [31]
  T. Suzuki, M. Yamamoto, Free Radic, Biol. Med. 88 (2015) 93–100.
32. [32]
  A.R. Vasconcelos, N.B. Dos Santos, C. Scavone, et al., Front. Pharmacol. 10 (2019) 33. doi: 10.3389/fphar.2019.00033
33. [33]
  Y.Y. Sun, H.J. Zhu, R.Y. Zhao, et al., Redox Biol. 66 (2023) 102852. doi: 10.1016/j.redox.2023.102852
34. [34]
  M. Xiang, Y. Lu, L. Xin, et al., Oxid. Med. Cell. Longev. 2021 (2021) 6614009. doi: 10.1155/2021/6614009
35. [35]
  J.W. Dong, H.F. Zhu, W.Z. Zhu, et al., Cell Res. 13 (2003) 385–391. doi: 10.1038/sj.cr.7290184
36. [36]
  S.C. Lo, X. Li, M.T. Henzl, et al., EMBO J. 25 (2006) 3605–3617. doi: 10.1038/sj.emboj.7601243
37. [37]
  F. Begnini, S. Geschwindner, P. Johansson, et al., J. Med. Chem. 65 (2022) 3473–3517. doi: 10.1021/acs.jmedchem.1c01975
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