Synthesis of tetra-substituted thiophene derivatives as potential Hits combating antibiotic resistant bacteria ESKAPE

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-02-01 DOI:10.1016/j.bioorg.2024.108101

Heba K. Abd El-Mawgoud , Asmaa M. AboulMagd , Ahmed M.M. Shaker , Magdy M. Hemdan , Aya I. Hassaballah , Paula S. Farag

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Abstract

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, different series of tetra-substituted thiophene derivatives were designed and synthesized by multi-component reactions (MCRs) in moderate to excellent yields. Some of the designed final compounds were synthesized by both microwave assisted method and traditional synthesis. Thirteen compounds were evaluated against antibiotic resistance bacteria ESKAPE, among which compounds 11, 13 and 17 showed the most potent inhibitory activities against multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 15.62, 7.61 and 15.62 µg/mL, respectively. Two potent candidates 11 and 13 not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human normal cells. Moreover, time dependent killing assay was performed that showed the reduction of the concentration of bacteria by 5.0 Log (CFU/mL) within 6 h, stronger than reference drug, ampicillin at the same concentration. Additionally, mechanistic investigation demonstrated that both compounds 11 and 13 could exert inhibitory activity against DHPS with IC₅₀ value of 1.73 and 4.67 µM, respectively and against DNA gyrase enzyme with IC₅₀ value of 0.07 and 0.04 µM, respectively. Moreover, the cytotoxic activity of the most active compound was crucial to be determined that showed IC₅₀ value of 75.42 µM. Molecular docking indicated that the binding of both compounds 11 and 13 to DHPS and DNA gyrase enzymes could hinder their function. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.

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抗耐药细菌ESKAPE的四取代噻吩衍生物的合成。

耐抗生素细菌的日益流行已导致严重的全球公共卫生问题；因此，迫切需要开发结构新颖的抗菌药物。在我们的研究中，设计并合成了不同系列的四取代噻吩衍生物的多组分反应（mcr）在中等至优良的收率。设计的一些最终化合物通过微波辅助法和传统合成法合成。13个化合物对耐药细菌ESKAPE的抑菌活性比较，其中化合物11、13和17对多重耐药粪肠球菌的抑菌活性最强，MIC值分别为15.62、7.61和15.62µg/mL。两种候选菌株11和13不仅表现出快速杀菌的特性，抑制粪肠球菌生物膜的形成，有效缓解耐药性的发展，而且对人体正常细胞的毒性也很低。同时进行时间依赖性杀菌实验，6 h内对细菌的杀伤效果为5.0 Log (CFU/mL)，比相同浓度的对照药氨苄西林更强。此外，机制研究表明，化合物11和13对DHPS的IC50值分别为1.73和4.67µM，对DNA旋切酶的IC50值分别为0.07和0.04µM。此外，最活性化合物的细胞毒活性至关重要，其IC50值为75.42µM。分子对接表明，化合物11和13与DHPS和DNA旋切酶结合会阻碍其功能。这些结果可以提供与现有抗生素化学结构不同的新型抗菌药物，为开发有效的抗耐药细菌抗生素开辟了广阔的前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.