Buono Alessandro, Diotallevi Aurora, Maestrini Sara, Verboni Michele, Kiuru Paula, Galluzzi Luca, Duranti Andrea, Olivieri Diego, Lucarini Simone
Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies, University of Urbino Carlo Bo, Campus Scientifico E. Mattei, via Ca' le suore 2, Urbino, 61029, Italy.
Department of Biomolecular Sciences, Section of Biochemistry and Biotechnology, University of Urbino Carlo Bo, Via Arco d'Augusto 2, Fano, 61032, Italy.
Chemistry. 2025 Aug 1;31(43):e202500637. doi: 10.1002/chem.202500637. Epub 2025 May 19.
Leishmaniasis is a neglected tropical disease which presents significant global health challenges due to the lack of effective vaccines and the limitations of existing chemotherapeutics in view of their toxicity, resistance, and high costs. In this study, we realized a library of novel bisindole derivatives as potential antileishmanial agents through a rapid Suzuki-Miyaura coupling reaction, utilizing NH-unprotected bromobisindole ethanamines and boronic acids. Optimization of reaction conditions allowed for the efficient and selective arylation of these substrates, with yields up to 93%. The compounds were screened for their activity against Leishmania infantum promastigotes. Among the tested bisindole derivatives, 3af (bearing a 4-vinylphenyl moiety) demonstrated potent antileishmanial activity (IC = 1.1 µM) with a higher selectivity index (21.8) compared to the reference drug miltefosine (9.8). A significant activity was also retained against intracellular amastigotes. This study establishes a robust methodology for late-stage functionalization of bisindoles, also highlighting these derivatives' potential as promising leads for antileishmanial drug development.
利什曼病是一种被忽视的热带疾病，由于缺乏有效的疫苗以及现有化疗药物在毒性、耐药性和高成本方面的局限性，它给全球健康带来了重大挑战。在本研究中，我们通过快速的铃木-宫浦偶联反应，利用未保护NH的溴代双吲哚乙胺和硼酸，实现了一个新型双吲哚衍生物库作为潜在的抗利什曼原虫剂。反应条件的优化使得这些底物能够高效、选择性地进行芳基化，产率高达93%。对这些化合物进行了抗婴儿利什曼原虫前鞭毛体活性的筛选。在测试的双吲哚衍生物中，3af（带有4-乙烯基苯基部分）表现出强大的抗利什曼原虫活性（IC = 1.1 µM），与参考药物米替福新（9.8）相比，具有更高的选择性指数（21.8）。对细胞内无鞭毛体也保留了显著活性。本研究建立了一种用于双吲哚后期功能化的稳健方法，同时也突出了这些衍生物作为抗利什曼病药物开发有前景的先导化合物的潜力。
