Departments of Chemistry and Biology, IRBM Spa, Via Pontina km 30, 600, 00071 Pomezia, Rome, Italy.
Departments of Chemistry and Biology, IRBM Spa, Via Pontina km 30, 600, 00071 Pomezia, Rome, Italy.
Bioorg Med Chem Lett. 2020 Apr 15;30(8):127052. doi: 10.1016/j.bmcl.2020.127052. Epub 2020 Feb 22.
The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC > 50 μM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.
本文描述了一种新型克氏锥虫生长抑制剂的鉴定，克氏锥虫是恰加斯病的病原体。对我们内部化合物库中的一组化合物进行体外筛选，针对寄生虫进行筛选，导致发现具有低微摩尔抑制克氏锥虫生长的命中化合物 1。对命中化合物进行 SAR 探索，鉴定出对寄生虫具有纳摩尔生长抑制作用（T. cruzi EC≤100nM）且对人细胞无细胞毒性（HeLa CC>50μM）的化合物。进一步的研究确定 CYP51 抑制（化合物 11CYP51 IC52nM）可能是这一新类抗寄生虫药物的作用机制之一。
