Procainamide-SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites
Procainamide-SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites
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DOI：
10.1021/acs.jmedchem.1c00821
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发表时间：
2021-06-29
影响因子：
7.3
通讯作者：
Arimondo, Paola B.
中科院分区：
文献类型：
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作者：
Nardella, Flore;Halby, Ludovic;Arimondo, Paola B.
表观遗传翻译后修饰对于人疟原虫在其生命周期中的存活和进展是必不可少的。在这里，我们提出了新的功能化辛二酰苯胺异羟肟酸（SAHA）衍生物，化学联合收割机的泛组蛋白脱乙酰酶抑制剂SAHA与DNA甲基转移酶抑制剂普鲁卡因胺。从廉价的原材料开始设计了三步或四步化学合成。与单一药物相比，组合分子在疟原虫中显示出上级活性，并且对人HDAC 6具有有效的抑制作用，在人细胞系中不产生细胞毒性。这些新化合物在柬埔寨多药耐药恶性疟原虫分离株中具有完全活性。它们通过诱导配子体中不可逆的形态学变化和抑制外鞭毛形成来靶向寄生虫的传播。这些化合物是缓慢作用的，与快速作用的青蒿素和双氢青蒿素联合使用时具有相加的抗疟作用。在严重疟疾模型中，先导化合物降低了小鼠的寄生虫血症。总之，这种新型融合分子为目前失败的抗疟治疗提供了一种负担得起的替代方案。
Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in Plasmodium and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Plasmodium falciparum Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.