Exploring hydrophilic 2,2-di

• Published in: PloS one 2024-06, Vol.19 (6), p.e0301901
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Computer software industry
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0301901

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 IC.sub.50 below 10 [mu]M. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC.sub.50 = 2.7 [mu]M) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC.sub.50 of 11.1 and 6.8 [mu]M 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.