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一种高效、简便的双吲哚甲烷的绿色合成方法,可作为潜在的 Mtb FtsZ 抑制剂。

An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors.

机构信息

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.

Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.

出版信息

Chem Biol Drug Des. 2018 Dec;92(6):1933-1939. doi: 10.1111/cbdd.13363. Epub 2018 Oct 11.

Abstract

The rising multidrug-resistant Mycobacterium tuberculosis (Mtb) strain made current anti-TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity. In the present study, we demonstrated for the first time bisindole derivatives as potential MtbFtsZ inhibitors. The synthesis of bisindole derivatives has been carried out using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Among the synthesized bisindole derivative, I16 and I5 showed 62.29% and 56.86% inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by two folds. Further compound I16 inhibited Mtb growth with a MIC of 37.5 μg/ml. To explain these interactions, detailed Molecular docking studies have been carried out and found to be supportive to the biological activity.

摘要

不断增加的耐多药结核分枝杆菌(Mtb)菌株使得当前的抗结核药物治疗无效,并成为全球主要的健康关注点;因此,开发针对关键靶标具有新机制的新分子至关重要。Mtb 丝状温度敏感蛋白 Z(FtsZ)是一种微管同源物,在 GTP 的存在下,它在细菌细胞分裂中起着重要作用,招募细胞分裂所必需的蛋白质,被认为是药物发现的潜在靶标。已知的大多数 MtbFtsZ 抑制剂都是来自天然资源的抗生素,存在细胞摄取、特异性等问题。在本研究中,我们首次证明了双吲哚衍生物是潜在的 MtbFtsZ 抑制剂。双吲哚衍生物的合成是通过在超声条件下使用钼酸铵作为催化剂采用绿色合成方法进行的。在合成的双吲哚衍生物中,I16 和 I5 对 MtbFtsZ 的 GTPase 活性的抑制率分别为 62.29%和 56.86%,并使分枝杆菌和枯草芽孢杆菌的长度增加了两倍。进一步的化合物 I16 以 MIC 为 37.5μg/ml 的浓度抑制了 Mtb 的生长。为了解释这些相互作用,我们进行了详细的分子对接研究,发现这些相互作用与生物活性相符。

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