Design and synthesis of novel hydroxamic acid derivatives based on quisinostat as promising antimalarial agents with improved safety
Design and synthesis of novel hydroxamic acid derivatives based on quisinostat as promising antimalarial agents with improved safety
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基于 quisinostat 的新型异羟肟酸衍生物的设计和合成，作为有前途的安全性更高的抗疟药
DOI：
10.15212/amm-2022-0007
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Xiaokang Li
中科院分区：
文献类型：
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作者：
Manjiong Wang;Tongke Tang;Zhenghui Huang;Ruoxi Li;Dazheng Ling;Jin Zhu;Lubin Jiang;Jian Li;Xiaokang Li
在我们之前的工作中，临床II期HDAC抑制剂奎尼司坦通过药物再利用策略被确定为一种有前景的抗疟疾药物，但其安全性令人担忧。在这里，进一步的药物化学方法被用来鉴定新的化学实体，比奎尼司坦更有效和更安全。本论文设计合成了38个新型异羟肟酸类化合物，并对其体外抗疟活性进行了系统的研究。这些化合物在纳摩尔浓度下对红细胞期的野生型和抗药性恶性疟原虫株有抑制作用。其中，化合物30口服后能完全清除感染约氏疟原虫的小鼠体内的寄生虫，并表现出比我们以前的工作更好的安全性和代谢特性。根据Western blotting，从机制上讲，化合物30上调了疟原虫组蛋白的乙酰化，从而表明它通过抑制恶性疟原虫HDAC酶而发挥抗疟疾作用。
In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through a drug repurposing strategy, but its safety was a matter of concern. Herein, further medicinal chemistry methods were used to identify new chemical entities with greater effectiveness and safety than quisinostat. In total, 38 novel hydroxamic acid derivatives were designed and synthesized, and their in vitro antimalarial activities were systematically investigated. These compounds at nanomolar concentrations showed inhibitory effects on wild-type and drug-resistant Plasmodium falciparum strains in the erythrocyte stage. Among them, compound 30 , after oral administration, resulted in complete elimination of parasites in mice infected with Plasmodium yoelii , and also exhibited better safety and metabolic properties than observed in our previous work. Mechanistically, compound 30 upregulated plasmodium histone acetylation, according to western blotting, thus suggesting that it exerts antimalarial effects through inhibition of Plasmodium falciparum HDAC enzymes.