Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation
Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation
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作为潜在抗疟药物的新型 FP-2 和 PfDHFR 双重抑制剂：设计、合成和生物学评价
DOI：
10.1016/j.cclet.2017.11.041
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Jin Zhu
中科院分区：
文献类型：
--
作者：
Wenhua Chen;Xue Yao;Zhenghui Huang;Fei Mao;Longfei Guan;Yun Tang;Hualiang Jiang;Jian Li;Jin Huang;Lubin Jiang;Jin Zhu
对疟疾寄生虫的抗药性已迅速发展到几乎所有使用的抗疟药物。半胱氨酸蛋白酶falcipain-2（FP-2）和恶性疟原虫二氢叶酸还原酶（PfDHFR）在恶性疟原虫的生命周期中起着至关重要的作用。本研究基于已报道的PfDHFR抑制剂和第一代FP-2和PfDHFR双重抑制剂的药效团一致性，通过片段组装鉴定了一系列新的双重抑制剂。筛选得到14个对FP-2和PfDHFR酶有较强抑制作用的化合物（IC 50分别为6.8 ± 1.8 μmol/L和8.8 ± 0.3 μmol/L），对P.恶性疟原虫3D 7株的IC_（50）为2.9 μmol/L。另外，14对氯喹抗性P. 14对两株临床分离株Fab 9（IC 50 = 2.6 μ mol/L）和GB 4（IC 50 = 1.0 μmol/L）均有微摩尔抑制作用。总的来说，这些数据表明14可能是治疗疟疾的良好先导化合物。
Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2 (FP-2) andPlasmodium falciparumdihydrofolate 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 of14, which showed potent inhibition against FP-2 and PfDHFR enzyme (IC50= 6.8 ± 1.8 μmol/L and IC50= 8.8 ± 0.3 μmol/L) andP. falciparum3D7 strain (IC50= 2.9 μmol/L). Additionally,14exhibited more potent inhibition to the proliferation of chloroquine-resistantP. falciparumDd2 strain (IC50= 1.1 μmol/L) than pyrimethamine (IC50> 10 μmol/L), and14displayed micromolar inhibitory activities against two clinical isolated strains Fab9 (IC50= 2.6 μmol/L) and GB4 (IC50= 1.0 μmol/L). Collectively, these data demonstrated that14might be a good lead compound for the treatment of malaria.
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DOI：
10.1007/978-3-030-33803-9_13
发表时间：
2020-01-03
期刊：
Highly Infectious Diseases in Critical Care
影响因子：
--
作者：
Hidalgo J;Arriaga P;Concejo BA
通讯作者：
Concejo BA
疟疾
DOI：
10.1007/s00108-006-1662-3
发表时间：
2006
期刊：
Der Internist
影响因子：
--
作者：
P. D. G. Burchard
通讯作者：
P. D. G. Burchard
影响因子：
81.5
作者：
Phillips, Margaret A.;Burrows, Jeremy N.;Wells, Timothy N. C.
通讯作者：
Wells, Timothy N. C.
影响因子：
9.1
作者：
Akhaja, Tarunkumar Nanjibhai;Raval, Jignesh Priyakant
通讯作者：
Raval, Jignesh Priyakant
影响因子：
3.4
作者：
Vincent T. Metzger;Changsun Eun;Peter M. Kekenes-Huskey;G. Huber;J. A. McCammon
通讯作者：
Vincent T. Metzger;Changsun Eun;Peter M. Kekenes-Huskey;G. Huber;J. A. McCammon