Centanni Alessia, Diotallevi Aurora, Buffi Gloria, Olivieri Diego, Santarém Nuno, Lehtinen Antti, Yli-Kauhaluoma Jari, Cordeiro-da-Silva Anabela, Kiuru Paula, Lucarini Simone, Galluzzi Luca
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino (PU), Italy.
PLoS One. 2024 Jun 13;19(6):e0301901. doi: 10.1371/journal.pone.0301901. eCollection 2024.
Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 μM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 μM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 μM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.
在此，我们报告了基于我们之前鉴定的抗利什曼原虫化合物URB1483（该化合物在初步体内试验中失败）设计并合成的一系列新的且更具亲水性的双吲哚类似物。对这些新型双吲哚进行了表型筛选，以检测其对婴儿利什曼原虫前鞭毛体的疗效，并同时检测其对人巨噬细胞样THP - 1细胞的毒性。在毒性较低的化合物中，有8种双吲哚的IC50低于10 μM。对选择性最高的化合物1h（选择性指数 = 10.1，与米替福新相当）和效力最强的化合物2c（IC50 = 2.7 μM）在婴儿利什曼原虫细胞内无鞭毛体上的疗效进行了测试。这些化合物在体外感染模型中也显示出了疗效，1h和2c的IC50分别为11.1和6.8 μM。此外，1h的毒性特征优于市售药物米替福新。基于所有这些原因，1h可能是一种新的亲水性抗利什曼原虫药物的起点，该药物对人巨噬细胞样细胞具有低细胞毒性。
