New thiophene–acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies,Chemical Biology & Drug Design

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New thiophene–acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-03-25 , DOI: 10.1111/cbdd.13176
Vanessa de Lima Serafim _{1,

2} , Mayara Barbalho Félix _{1,

2} , Daiana Karla Frade Silva _{1,

2} , Klinger Antônio da Franca Rodrigues _{1,

2} , Patrícia Néris Andrade _{1,

2} , Sinara Mônica Vitalino de Almeida ₃ , Sanderssonilo de Albuquerque dos Santos ₄ , Jamerson Ferreira de Oliveira ₄ , Maria do Carmo Alves de Lima ₄ , Francisco Jaime Bezerra Mendonça-Junior _{2,

5} , Marcus Tullius Scotti ₂ , Márcia Rosa de Oliveira ₁ , Ricardo Olímpio de Moura _{5,

6}

Affiliation

In this study, we synthesized eight new compounds containing the 2‐amino‐cycloalkyl[b]thiophene and acridine moieties (ACT₀₁ and ACS₀₁‐ACS₀₇). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS₀₁ and ACS₀₂ derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC₅₀ values of 9.60 ± 3.19 and 10.95 ± 3.96 μm. Additionally, these two derivatives were effective against antimony‐resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS₀₁ is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 10⁴ m⁻¹. In partial least‐squares studies, it was observed that the most active compounds (ACS₀₁ and ACS₀₂) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene–acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene–acridine derivatives are promising molecules as potential drug candidates.

中文翻译：

新型噻吩–啶化合物：合成，抗疟疾活性，DNA结合，化学计量学和分子对接研究

在这项研究中，我们合成了8个新的化合物，其中包含2-氨基-环烷基[b]噻吩和a啶部分（ACT ₀₁和ACS ₀₁ - ACS ₀₇）。所测试的化合物均未显示出人类红细胞的细胞毒性。这些新化合物呈现antipromastigote活性，其中ACS ₀₁和ACS ₀₂衍生物呈现显著antileishmanial活性，具有比参考药物更好的性能（三和五价锑），与相应的IC ₅₀为9.60±3.19和10.95±3.96μ值米。此外，这两种衍生物对抗锑耐药的利什曼原虫（Leishmania）也有效亚马逊菌株。另外，进行结合和断裂DNA测定。观察到ACS ₀₁的抗菌活性与前鞭毛体形式的DNA断裂无关。但是，它以10 ⁴ m ^-1的结合常数与DNA相互作用。在部分最小二乘研究中，观察到活性最高的化合物（ACS ₀₁和ACS ₀₂）显示出较低的两亲性矩描述子值，但分子的亲脂性与抗菌活性之间存在相关性。此外，对接分子研究表明，噻吩–啶衍生物与丙酮酸激酶活性部位之间有相互作用，其中天冬酰胺152残基主要与噻吩部分相互作用。因此，结果表明，新的噻吩–啶衍生物是有望成为潜在药物候选分子的分子。

更新日期：2018-03-25

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