Cyclic tetrapeptide histone deacetylase inhibitors represent a promising class of antiplasmodial agents that epigenetically disrupt a wide range of cellular processes in Plasmodium falciparum. Unfortunately, certain limitations, including reversible killing effects and host cell toxicity, prevented these inhibitors from further development and clinical use as antimalarials. In this study, we present a series of cyclic tetrapeptide analogues derived primarily from the fungus Wardomyces dimerus that inhibit P. falciparum with low nanomolar potency and high selectivity. This cyclic tetrapeptide scaffold was diversified further via semisynthesis, leading to the identification of several key structural changes that positively impacted the selectivity, potency, and in vitro killing profiles of these compounds. We confirmed their effectiveness as HDAC inhibitors through the inhibition of PfHDAC1 catalytic activity, in silico modeling, and the hyperacetylation of histone H4. Additional analysis revealed the in vitro inhibition of the most active epoxide-containing analogue was plasmodistatic, exhibiting reversible inhibitory effects upon compound withdrawal after 24 or 48 h. In contrast, one of the new diacetyloxy semisynthetic analogues, CTP-NPDG 19, displayed a rapid and irreversible action against the parasite following compound exposure for 24 h.

中文翻译：

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具有改善的恶性疟原虫选择性和杀灭谱的环状四肽 HDAC 抑制剂

环状四肽组蛋白脱乙酰酶抑制剂代表了一类有前途的抗疟原虫药物，可在表观遗传上破坏恶性疟原虫的广泛细胞过程。不幸的是，某些限制，包括可逆的杀伤作用和宿主细胞毒性，阻止了这些抑制剂作为抗疟药的进一步开发和临床应用。在这项研究中，我们提出了一系列主要来自真菌Wardomyces dimerus的环状四肽类似物，它们可抑制恶性疟原虫。具有低纳摩尔效价和高选择性。这种环状四肽支架通过半合成进一步多样化，从而确定了几个对这些化合物的选择性、效力和体外杀伤谱产生积极影响的关键结构变化。我们通过抑制Pf HDAC1 催化活性、计算机建模和组蛋白 H4 的超乙酰化证实了它们作为 HDAC 抑制剂的有效性。额外的分析揭示了体外最活跃的含环氧化物类似物的抑制作用是抑制疟原虫，在 24 或 48 小时后停用化合物时表现出可逆的抑制作用。相比之下，一种新的二乙酰氧基半合成类似物 CTP-NPDG 19 在化合物暴露 24 小时后对寄生虫表现出快速且不可逆的作用。