Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil.
Departamento de Medicina Veterinária, Faculdade de Medicina, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.
Chem Biol Drug Des. 2024 Jul;104(1):e14585. doi: 10.1111/cbdd.14585.
Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC values of 28.86 and 7.70 μM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.
利什曼病是一种由原生动物利什曼原虫引起的疾病，被认为是一个重大且紧迫的公共卫生问题，主要发生在发展中国家。由于缺乏有效的疫苗，治疗感染者是控制这种疾病最常用的预防措施之一。然而，治疗方法的选择非常有限，这些药物存在严重的副作用和疗效的可变性。为了解决这个问题，在这项工作中，我们合成了一系列苯并噻唑衍生物，并对亚马逊利什曼原虫的前鞭毛体和内阿米巴体进行了检测，同时还检测了它们对巨噬细胞的毒性。此外，我们还进行了关于作用机制的研究。在合成的分子中，苯环 4 位的取代似乎对活性至关重要。最佳化合物对亚马逊利什曼原虫的前鞭毛体和内阿米巴体的 IC 值分别为 28.86 和 7.70 μM，比米替福新（作为参考药物）更有效。该化合物的理化性质和药代动力学（ADMET）特性的计算分析表明，它具有良好的口服生物利用度和安全性。总之，在寻找新的抗利什曼病药物时，使用苯并噻唑核的策略是有利的，初步数据提供了关于作用机制的信息，计算参数也表明该化合物具有良好的临床前研究前景。
