探索酰基硫代三嗪吲哚类药物:针对脲酶、α-淀粉酶、α-葡萄糖苷酶、抗菌剂和抗氧化剂靶点的设计、合成和 SAR 研究,以及分子对接和生物活性分析。

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mian Bilal Haider, Aamer Saeed, Atteeque Ahmed, Muhammad Azeem, Hammad Ismail, Sabba Mehmood, Parham Taslimi, Syed Adnan Ali Shah, Madiha Irfan, Hesham R. El-Seedi
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引用次数: 0

摘要

通过一系列五个步骤,以经济的起始材料伊沙替丁(Isatin)为原料,合成了一个基于酰基硫代三嗪吲哚(ATTI)的生物活性支架的小型化学库。首先对伊沙替丁进行硝化,然后通过亲核取代反应连接戊基。得到的化合物与硫代氨基脲反应得到硫代氨基脲衍生物,最后在水作为溶剂的碱性条件下进行环化反应。最后,通过硝化的噻三嗪吲哚分子与不同取代的苯酰溴反应,得到了所报告的系列化合物。利用核磁共振光谱和元素分析对合成的化合物进行了表征。最后,仔细研究了合成图案对脲酶、α-葡萄糖苷酶、DPPH 和 α-淀粉酶的潜在阻碍作用。对脲酶、α-葡萄糖苷酶和 DPPH 的 IC50 值分别为 29.7 ± 0.8、20.5 ± 0.5 和 36.8 ± 3.9 µM。同时,对于α-淀粉酶,在苯环上具有对-CH3的化合物 5 g 的活性最高,计算得出的 IC50 值为 90.3 ± 1.1 µM。此外,还测定了这些支架的抗真菌和抗细菌活性。在测试的菌株中,以溴为取代基的 5d 表现出了最强的抗菌活性,同时它对烟曲霉的效力也最高。其他衍生物 5b、5e、5i 和 5j 也表现出对抗菌和抗真菌菌株的双重抑制作用。这些衍生物的相互作用模式清楚地表明了它们的 SAR 特性,它们的对接得分与其 IC50 值相关。分子对接研究进一步证实了氢键等相互作用的重要性。各种取代基的电子因子在配体和目标物之间产生了各种相互作用,这意味着它们在合成的杂环支架结构中的重要性。总之,合成的化合物对各种重要靶标具有令人满意的生物活性。因此,我们鼓励通过在结构的不同位置添加不同的取代基来提高这些化合物的活性,从而开展进一步的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Exploring Acyl Thiotriazinoindole Based Pharmacophores: Design, Synthesis, and SAR Studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets

Exploring Acyl Thiotriazinoindole Based Pharmacophores: Design, Synthesis, and SAR Studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets

A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.

Graphical Abstract

Exploring Acyl Thiotriazinoindole based Pharmacophores: Design, Synthesis, and SAR studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets

An updated synthetic pathway to furnish acyl thiotriazinoindole based scaffolds was developed starting from Isatin and the novel compounds were assessed for various biological applications.

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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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