Laboratório de Síntese de Candidatos a Fármacos (LaSFar), Instituto de Química, Universidade Federal de Uberlândia (UFU), Uberlândia, MG 38400-902, Brazil.
Grupo de Genômica Funcional de Parasitos, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte, MG 30190-002, Brazil.
Bioorg Med Chem. 2024 May 1;105:117736. doi: 10.1016/j.bmc.2024.117736. Epub 2024 Apr 24.
Leishmaniasis and Chagas disease are neglected tropical diseases caused by Trypanosomatidae parasites. Given the numerous limitations associated with current treatments, such as extended treatment duration, variable efficacy, and severe side effects, there is an urgent imperative to explore novel therapeutic options. This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in the fight against Chagas disease and leishmaniasis.
利什曼病和恰加斯病是由锥虫引起的被忽视的热带病。鉴于目前治疗方法存在许多局限性，如治疗时间延长、疗效不一和严重的副作用，因此迫切需要探索新的治疗选择。本研究详细介绍了苯磺酰衍生物（称为起始命中）针对 Trypanossoma cruzi（T. cruzi）、Leishmania infantum（L. infantum）和 Leishmania braziliensis（L. braziliensis）的命中到先导优化的早期阶段。我们使用一系列 26 种新设计的衍生物研究了结构-活性关系，最终得到了具有潜在的先导候选物，对 T. cruzi 和 Leishmania spp. 的活性分别为低微摩尔和亚微摩尔，对哺乳动物细胞的体外细胞毒性低。这些发现强调了该类化学物质在对抗恰加斯病和利什曼病方面的巨大潜力。
