Citation: Chen Wenhua, Yao Xue, Huang Zhenghui, Mao Fei, Guan Longfei, Tang Yun, Jiang Hualiang, Li Jian, Huang Jin, Jiang Lubin, Zhu Jin. Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation[J]. Chinese Chemical Letters, ;2019, 30(1): 250-254. doi: 10.1016/j.cclet.2017.11.041 shu

Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation

Chen Wenhua ^a ,
Yao Xue ^a ,
Huang Zhenghui ^b ,
Mao Fei ^a ,
Guan Longfei ^a ,
Tang Yun ^a ,
Jiang Hualiang ^a ,
Li Jian ^a ,
Huang Jin ^a,, ,
Jiang Lubin ^b,, ,
Zhu Jin ^a,,

a.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b.
Key Laboratory of Molecular Virology & Immunology, Unit of Human Parasite Molecular and Cell Biology, Institute Pasteur of Shanghai, University of Chinese Academy of Science, Shanghai 200031, China

Corresponding author: Huang Jin, huangjin@ecust.edu.cn Jiang Lubin, lbjiang@ips.ac.cn Zhu Jin, jinz@ecust.edu.cn
Received Date: 27 September 2017
Revised Date: 25 November 2017
Accepted Date: 30 November 2017
Available Online: 5 January 2017

Figures(3)

Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme (IC₅₀=6.8±1.8 mmol/L and IC₅₀=8.8±0.3 mmol/L) and P. falciparum 3D7 strain (IC₅₀=2.9 mmol/L). Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P. falciparum Dd2 strain (IC₅₀=1.1 mmol/L) than pyrimethamine (IC₅₀ >10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC₅₀=2.6 mmol/L) and GB4 (IC₅₀=1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.
- Antimalarial drug,
- Plasmodium falciparum,
- FP-2,
- PfDHFR,
- Dual inhibitor
1. [1]
  A. Persidis, Nat. Biotechnol. 18(2000) 111-112. doi: 10.1038/71816
2. [2]
  N.A. Tarunkumar, P.R. Jignesh, Chin. Chem. Lett. 23(2012) 785-788. doi: 10.1016/j.cclet.2012.05.004
3. [3]
  T. Conroy, J.T. Guo, N. Elias, et al., J. Med. Chem. 57(2014) 10557-10563. doi: 10.1021/jm501439w
4. [4]
  P.J. Hotez, B. Pecoul, PLoS Negl. Trop. Dis. 4(2010) e718. doi: 10.1371/journal.pntd.0000718
5. [5]
  World Malaria Report 2016, World Health Organization, Geneva, 2016. http://www.who.int/malaria/publications/world-malaria-report-2016/en/.
6. [6]
  L. Musset, O. Bouchaud, S. Matheron, et al., Microbes Infect. 8(2006) 2599-2604. doi: 10.1016/j.micinf.2006.07.011
7. [7]
  A.M. Dondorp, F. Nosten, P. Yi, et al., N. Engl. J. Med. 361(2009) 455-467. doi: 10.1056/NEJMoa0808859
8. [8]
  A.M. Dondorp, S. Yeung, L. White, et al., Nat. Rev. Microbiol. 8(2010) 272-280. doi: 10.1038/nrmicro2331
9. [9]
  K.T. Andrews, G. Fisher, T.S. Skinner-Adams, Int. J. Parasitol.:Drugs Drug Resist. 4(2014) 95-111. doi: 10.1016/j.ijpddr.2014.02.002
10. [10]
  S.C. Stolze, E. Deu, F. Kaschani, et al., Chem. Biol. 9(2012) 1546-1555.
11. [11]
  T.M. Musyoka, A.M. Kanzi, K.A. Lobb, et al., J. Biomol. Struct. Dyn. 35(2016) 2084-2101.
12. [12]
  C.V. Plowe, J.G. Kublin, O.K. Doumbo, Drug Resist. Updates 1(1998) 389-396. doi: 10.1016/S1368-7646(98)80014-9
13. [13]
  K.J. Gresty, K.A. Gray, A. Bobogare, et al., Malar. J. 13(2014) 402-408. doi: 10.1186/1475-2875-13-402
14. [14]
  V.T. Metzger, C. Eun, P.M. Kekenes-Huskey, et al., Biophys. J. 107(2014) 2394-2402. doi: 10.1016/j.bpj.2014.09.039
15. [15]
  H. Huang, W.Q. Lu, X. Li, et al., Bioorg. Med. Chem. Lett. 22(2012) 958-962. doi: 10.1016/j.bmcl.2011.12.011
16. [16]
  Y.Q. Yang, Y. Yu, X.L. Li, et al., J. Med. Chem. 60(2017) 1994-2005. doi: 10.1021/acs.jmedchem.6b01733
17. [17]
  N.A. Malmquist, T.A. Moss, S. Mecheri, et al., Proc. Natl. Acad. Sci. U. S. A. 109(2012) 16708-16713. doi: 10.1073/pnas.1205414109
1. [1]
  Cheng-Zhe Gao , Hao-Ran Jia , Tian-Yu Wang , Xiao-Yu Zhu , Xiaofeng Han , Fu-Gen Wu . A dual drug-loaded tumor vasculature-targeting liposome for tumor vasculature disruption and hypoxia-enhanced chemotherapy. Chinese Chemical Letters, 2025, 36(1): 109840-. doi: 10.1016/j.cclet.2024.109840
2. [2]
  Jia Chen , Yun Liu , Zerong Long , Yan Li , Hongdeng Qiu . Colorimetric detection of α-glucosidase activity using Ni-CeO₂ nanorods and its application to potential natural inhibitor screening. Chinese Chemical Letters, 2024, 35(9): 109463-. doi: 10.1016/j.cclet.2023.109463
3. [3]
  Shuheng Zhang , Yuanyuan Zhang , Wanyu Wang , Yuzhu Hu , Xinchuan Chen , Bilan Wang , Xiang Gao . A combination strategy of DOX and VEGFR-2 targeted inhibitor based on nanomicelle for enhancing lymphoma therapy. Chinese Chemical Letters, 2024, 35(12): 109658-. doi: 10.1016/j.cclet.2024.109658
4. [4]
  Yuhao Guo , Na Li , Tingjiang Yan . Tandem catalysis for photoreduction of CO2 into multi-carbon fuels on atomically thin dual-metal phosphochalcogenides. Chinese Journal of Structural Chemistry, 2024, 43(7): 100320-100320. doi: 10.1016/j.cjsc.2024.100320
5. [5]
  Tinghui Yang , Min Kuang , Jianping Yang . Mesoporous CuCe dual-metal catalysts for efficient electrochemical reduction of CO2 to methane. Chinese Journal of Structural Chemistry, 2024, 43(8): 100350-100350. doi: 10.1016/j.cjsc.2024.100350
6. [6]
  Yuan Teng , Zichun Zhou , Jinghua Chen , Siying Huang , Hongyan Chen , Daibin Kuang . Dual atom-bridge effect promoting interfacial charge transfer in 2D/2D Cs₃Bi₂Br₉/BiOBr epitaxial heterojunction for efficient photocatalysis. Chinese Chemical Letters, 2025, 36(2): 110430-. doi: 10.1016/j.cclet.2024.110430
7. [7]
  Zhenchun Yang , Bixiao Guo , Zhenyu Hu , Kun Wang , Jiahao Cui , Lina Li , Chun Hu , Yubao Zhao . Molecular engineering towards dual surface local polarization sites on poly(heptazine imide) framework for boosting H₂O₂ photo-production. Chinese Chemical Letters, 2024, 35(8): 109251-. doi: 10.1016/j.cclet.2023.109251
8. [8]
  Linghui Zou , Meng Cheng , Kaili Hu , Jianfang Feng , Liangxing Tu . Vesicular drug delivery systems for oral absorption enhancement. Chinese Chemical Letters, 2024, 35(7): 109129-. doi: 10.1016/j.cclet.2023.109129
9. [9]
  Fengjie Liu , Fansu Meng , Zhenjiang Yang , Huan Wang , Yuehong Ren , Yu Cai , Xingwang Zhang . Exosome-biomimetic nanocarriers for oral drug delivery. Chinese Chemical Letters, 2024, 35(9): 109335-. doi: 10.1016/j.cclet.2023.109335
10. [10]
  Yulong Shi , Fenbei Chen , Mengyuan Wu , Xin Zhang , Runze Meng , Kun Wang , Yan Wang , Yuheng Mei , Qionglu Duan , Yinghong Li , Rongmei Gao , Yuhuan Li , Hongbin Deng , Jiandong Jiang , Yanxiang Wang , Danqing Song . Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1. Chinese Chemical Letters, 2024, 35(5): 108792-. doi: 10.1016/j.cclet.2023.108792
11. [11]
  Gengchen Guo , Tianyu Zhao , Ruichang Sun , Mingzhe Song , Hongyu Liu , Sen Wang , Jingwen Li , Jingbin Zeng . Au-Fe₃O₄ dumbbell-like nanoparticles based lateral flow immunoassay for colorimetric and photothermal dual-mode detection of SARS-CoV-2 spike protein. Chinese Chemical Letters, 2024, 35(6): 109198-. doi: 10.1016/j.cclet.2023.109198
12. [12]
  Guangchang Yang , Shenglong Yang , Jinlian Yu , Yishun Xie , Chunlei Tan , Feiyan Lai , Qianqian Jin , Hongqiang Wang , Xiaohui Zhang . Regulating local chemical environment in O3-type layered sodium oxides by dual-site Mg²⁺/B³⁺ substitution achieves durable and high-rate cathode. Chinese Chemical Letters, 2024, 35(9): 109722-. doi: 10.1016/j.cclet.2024.109722
13. [13]
  Xi Tang , Chunlei Zhu , Yulu Yang , Shihan Qi , Mengqiu Cai , Abdullah N. Alodhayb , Jianmin Ma . Additive regulating Li⁺ solvation structure to construct dual LiF−rich electrode electrolyte interphases for sustaining 4.6 V Li||LiCoO₂ batteries. Chinese Chemical Letters, 2024, 35(12): 110014-. doi: 10.1016/j.cclet.2024.110014
14. [14]
  Yiran Tao , Chunlei Dai , Zhaoxiang Xie , Xinru You , Kaiwen Li , Jun Wu , Hai Huang . Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer. Chinese Chemical Letters, 2024, 35(8): 109170-. doi: 10.1016/j.cclet.2023.109170
15. [15]
  Chao Chen , Wenwen Yu , Guangen Huang , Xuelian Ren , Xiangli Chen , Yixin Li , Shenggui Liang , Mengmeng Xu , Mingyue Zheng , Yaxi Yang , He Huang , Wei Tang , Bing Zhou . Asymmetric macrocyclization enabled by Rh(Ⅲ)-catalyzed CH activation: Enantioenriched macrocyclic inhibitor of Zika virus infection. Chinese Chemical Letters, 2024, 35(11): 109574-. doi: 10.1016/j.cclet.2024.109574
16. [16]
  Yujie Li , Ya-Nan Wang , Yin-Gen Luo , Hongcai Yang , Jinrui Ren , Xiao Li . Advances in synthetic biology-based drug delivery systems for disease treatment. Chinese Chemical Letters, 2024, 35(11): 109576-. doi: 10.1016/j.cclet.2024.109576
17. [17]
  Shaoqing Du , Xinyong Liu , Xueping Hu , Peng Zhan . Targeting novel sites represents an effective strategy for combating drug resistance. Chinese Chemical Letters, 2025, 36(1): 110378-. doi: 10.1016/j.cclet.2024.110378
18. [18]
  Jisheng Liu , Junli Chen , Xifeng Zhang , Yin Wu , Xin Qi , Jie Wang , Xiang Gao . Red blood cell membrane-coated FLT3 inhibitor nanoparticles to enhance FLT3-ITD acute myeloid leukemia treatment. Chinese Chemical Letters, 2024, 35(9): 109779-. doi: 10.1016/j.cclet.2024.109779
19. [19]
  Ningyue Xu , Jun Wang , Lei Liu , Changyang Gong . Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy: A review of recent advances. Chinese Chemical Letters, 2024, 35(8): 109225-. doi: 10.1016/j.cclet.2023.109225
20. [20]
  Yihan Zhou , Duo Gao , Yaying Wang , Li Liang , Qingyu Zhang , Wenwen Han , Jie Wang , Chunliu Zhu , Xinxin Zhang , Yong Gan . Worm-like micelles facilitate the intestinal mucus diffusion and drug accumulation for enhancing colorectal cancer therapy. Chinese Chemical Letters, 2024, 35(6): 108967-. doi: 10.1016/j.cclet.2023.108967

Get Citation

PDF

XML

Metrics

PDF Downloads(2)
Abstract views(658)
HTML views(28)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142