Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy.
Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185 Rome, Italy.
ACS Infect Dis. 2022 Jul 8;8(7):1356-1366. doi: 10.1021/acsinfecdis.2c00232. Epub 2022 Jun 22.
Neglected tropical diseases (NTDs), including trypanosomiasis, leishmaniasis, and schistosomiasis, result in a significant burden in terms of morbidity and mortality worldwide every year. Current antiparasitic drugs suffer from several limitations such as toxicity, no efficacy toward all of the forms of the parasites' life cycle, and/or induction of resistance. Histone-modifying enzymes play a crucial role in parasite growth and survival; thus, the use of epigenetic drugs has been suggested as a strategy for the treatment of NTDs. We tested structurally different HDACi -, chosen from our in-house library or newly synthesized, against spp, and . Among them, emerged as the most potent against all of the tested parasites, but it was too toxic against host cells, hampering further studies. The retinoic 2'-aminoanilide was less potent than in all parasitic assays, but as its toxicity is considerably lower, it could be the starting structure for further development. In , compound exhibited a single-digit micromolar inhibition of parasite growth combined with moderate toxicity. In , 's close analogs - were tested in new transformed schistosomula (NTS) and adult worms displaying high death induction against both parasite forms. Among them, and exhibited very low toxicity in human retinal pigment epithelial (RPE) cells, thus being promising compounds for further optimization.
被忽视的热带病（NTDs），包括锥虫病、利什曼病和血吸虫病，每年在全球范围内都给发病率和死亡率带来了巨大的负担。目前的抗寄生虫药物存在多种局限性，如毒性、对寄生虫生命周期所有形式均无疗效和/或诱导耐药性。组蛋白修饰酶在寄生虫的生长和存活中起着至关重要的作用；因此，人们提出使用表观遗传药物作为治疗 NTDs 的一种策略。我们测试了结构不同的 HDACi - ，这些抑制剂是从我们的内部库中选择的或新合成的，针对 spp 和. 在这些抑制剂中， 对所有测试的寄生虫都表现出最强的活性，但对宿主细胞的毒性太大，阻碍了进一步的研究。维甲酸 2'-氨基苯甲酰胺 不如 在所有寄生虫检测中有效，但由于其毒性要低得多，它可能成为进一步开发的起始结构。在 中，化合物 对寄生虫生长的抑制作用在微摩尔范围内，同时具有中等毒性。在 中，测试了 的类似物 - ，它们对新转化的血吸虫（NTS）和成虫都有很高的致死诱导作用，对两种寄生虫形式都有很高的致死诱导作用。其中， 和 对人视网膜色素上皮（RPE）细胞的毒性非常低，因此是进一步优化的有前途的化合物。
