We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I₂, is a precursor of the anticancer duocarmycin family that preserves the class's sequence-specific DNA binding but lacks its signature DNA alkylating cyclopropyl warhead. While less active than duocarmycin, PDE-I₂ retains comparable antimalarial potency to chloroquine. Importantly, PDE-I₂ is >1,000-fold less toxic to human cell lines than duocarmycin, with mitigated impacts on eukaryotic chromosome stability. PDE-I₂ treatment induces severe defects in parasite nuclear segregation leading to impaired daughter cell formation during schizogony. Time-of-addition studies implicate parasite DNA metabolism as the target of PDE-I₂, with defects observed in DNA replication and chromosome integrity. We find the effect of duocarmycin and PDE-I₂ on parasites is phenotypically indistinguishable, indicating that the DNA binding specificity of duocarmycins is sufficient and the genotoxic cyclopropyl warhead is dispensable for the parasite-specific selectivity of this compound class.

我们从微生物天然产物提取物的筛选中鉴定出一种选择性的纳摩尔血期疟疾增殖抑制剂。负责的化合物 PDE-I ₂是抗癌多卡霉素家族的前体，它保留了该类的序列特异性 DNA 结合，但缺乏其标志性的 DNA 烷基化环丙基弹头。尽管 PDE-I 2 的活性不如多卡霉素，但 PDE-I ₂的抗疟效力与氯喹相当。重要的是，PDE-I ₂对人类细胞系的毒性比多卡霉素低 1,000 倍以上，对真核细胞染色体稳定性的影响减轻。PDE-I ₂处理会导致寄生虫核分离的严重缺陷，导致分裂期间子细胞形成受损。加法时间研究表明寄生虫 DNA 代谢是 PDE-I ₂的目标，在 DNA 复制和染色体完整性方面观察到缺陷。我们发现多卡霉素和 PDE-I ₂对寄生虫的影响在表型上无法区分，这表明多卡霉素的 DNA 结合特异性是足够的，遗传毒性环丙基弹头对于此类化合物的寄生虫特异性选择性是可有可无的。