第二代Falcipain–2和PfDHFR双重抑制剂的设计、合成及其生物学评价

Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of drugs with new mechanism to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. Falcipain–2 (FP–2) and PfDHFR have crucial roles and are absolutely necessary in the parasite life cycle. Thus, a more powerful pesticidal effect could be achieved by inhibition of FP–2 and PfDHFR simultaneously. Such dual inhibitors could show good synergetic effect and overcome the drug-resistance, and might be capable of providing “combination therapy” in a single agent. In this project, based on the structures of some uniform pharmacophores of potent PfDHFR inhibitors reported in literatures and first-generation dual inhibitors of FP–2 and PfDHFR identified by us previously, which have relative weak inhibitory activity against PfDHFR, a series of novel second-generation dual inhibitors of FP–2 and PfDHFR have been designed through pharmacophore assembly. With the help of molecular docking, we will carry out structure optimization and SAR research, and try to identify novel dual inhibitors of FP-2 and DHFR with more potent activities in vitro and in vivo. Furthermore, this project will provide new paradigm for the development of novel antimalarial agents and instructive clues for resolving the ever-increasing drug-resistance of plasmodium.

疟疾耐药性已波及到几乎所有现存的抗疟药物，开发新机制的抗疟药物，尤其是针对多靶点的药物，来延缓疟疾耐药问题显得日益迫切。Falcipain–2 (FP-2)和PfDHFR是恶性疟原虫生命周期至关重要且必不可少的酶。FP–2和PfDHFR双重抑制剂将双重阻断疟原虫的生长和繁殖，以单分子“组合治疗”的方式起到协同增效的杀虫效果，有利于延缓耐药性的产生。考虑到前期我们发现的第一代FP–2和PfDHFR双重抑制剂对PfDHFR的抑制活性相对较弱的缺点，本项目将文献报道的强效PfDHFR抑制剂的活性药效团共性片段(如2,4-二氨基喹唑啉)，巧妙拼合到第二代双重抑制剂结构中，并应用计算机分子对接手段进行初步评价和遴选，继而开展构效关系研究。以期获得体内外活性俱佳的新颖结构FP–2和PfDHFR双重抑制剂。本项目的实施为新型抗疟药物的开发提供结构基础，同时也为解决日益严重的疟原虫耐药性问题提供新的思路。

疟疾耐药性已波及到几乎所有现存的抗疟药物，开发新机制的抗疟药物，尤其是针对多靶点的药物，来延缓疟疾耐药问题显得日益迫切。Falcipain-2 (FP-2)和PfDHFR是恶性疟原虫生命周期至关重要且必不可少的酶。FP-2和PfDHFR双重抑制剂将双重阻断疟原虫的生长和繁殖，以单分子“组合治疗”的方式起到协同增效的杀虫效果，有利于延缓耐药性的产生。本课题在我们前期首次发现的第一代FP-2和PfDHFR双重抑制剂的SAR基础上，结合电子等排替换、药效团拼合和分子对接模拟预测，设计、合成了57个第二代FP-2和PfDHFR双重抑制剂。酶水平抑制实验发现了11个新颖结构、强效的小分子FP-2 (IC50=4.9~10.0 μM)和PfDHFR (IC50=0.0262~8.8 μM)双重抑制剂。体外恶性疟原虫生长抑制实验发现了2个2,4-二氨基喹唑啉类化合物(HL041244和HL041251)对敏感株恶性疟原虫3D7C8具有强效的体外杀虫活性(3D7C8: EC50=54.22~61.73 nM)，并且对耐氯喹恶性疟原虫Dd2均有效(Dd2: EC50=1.20~2.18 μM)。进一步小鼠体内杀疟原虫活性测试发现，HL041251具有强效的体内杀虫药效(20 mg/kg，减虫率>90%)，活性结果优于同等剂量的青蒿素和HL041244。进一步发现HL041251对两株临床恶性疟原虫均有效(Fab9：IC50=14.2 nM，GB4：IC50=23.4 nM)。本项目共发表3篇SCI论文，申请中国发明专利2项，协助培养博士研究生3名。本项目研究结果为新型抗疟药物的开发提供结构基础，同时也为解决日益严重的疟原虫耐药性问题提供新的思路。

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