具有芳香族腙分子的苯并噻唑衍生物--一类新的抗利什曼病化合物--的合成、生物学评价和作用机理。

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elaine Soares Coimbra, Luciana M. R. Antinarelli, Ari Sérgio de Oliveira Lemos, Adolfo Firmino da Silva Neto, Alessandra Campbell Pinheiro, Marcus Vinícius Nora de Souza
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引用次数: 0

摘要

利什曼病是一种由原生动物利什曼原虫引起的疾病,被认为是主要发生在发展中国家的一个重大而紧迫的公共卫生问题。在缺乏有效疫苗的情况下,对感染者进行治疗是控制这种疾病最常用的预防措施之一。然而,治疗手段仅限于几种药物,副作用严重,疗效也参差不齐。为了解决这个问题,在这项工作中,合成了一系列苯并噻唑衍生物,并检测了它们对亚马逊嗜血杆菌原虫和细胞内母细胞的毒性,以及对巨噬细胞的毒性。此外,还对其作用机制进行了研究。在合成的分子中,芳环第 4 位的取代似乎对活性至关重要。最佳化合物对亚马逊蝇原体和非原体的 IC50 值分别为 28.86 和 7.70 μM,活性高于作为参考药物的米替福新。对该化合物的理化和药代动力学(ADMET)特性进行的硅学分析表明,该化合物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的过程中,使用苯并噻唑核素的策略是有利的,初步数据提供了有关其作用机制的信息,硅学参数也表明该化合物具有良好的临床前研究特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds

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 IC50 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.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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