Synthesis and anti-ureolitic activity of Biginelli adducts derived from formylphenyl boronic acids

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-08-23 DOI:10.1016/j.bioorg.2024.107735

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Abstract

Urease is a metalloenzyme that contains two Ni(II) ions in its active site and catalyzes the hydrolysis of urea into ammonia and carbon dioxide. The development of effective urease inhibitors is crucial not only for mitigating nitrogen losses in agriculture but also for offering an alternative treatment against infections caused by resistant pathogens that utilize urease as a virulence factor. This study focuses on synthesizing and investigating the urease inhibition potential of Biginelli Adducts bearing a boric acid group. An unsubstituted or hydroxy-substituted boronic group in the Biginelli adducts structure enhances the urease inhibitory activity. Biophysical and kinetics studies revealed that the best Biginelli adduct (4e; IC₅₀ = 132 ± 12 µmol/L) is a mixed inhibitor with higher affinity to the urease active site over an allosteric one. Docking studies confirm the interactions of 4e with residues essential for urease activity and demonstrate its potential to coordinate with the nickel atoms through the oxygen atoms of carbonyl or boronic acid groups. Overall, the Biginelli adduct 4e shows great potential as an additive for developing enhanced efficiency fertilizers and/or for medical applications.

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由甲酰苯基硼酸衍生的 Biginelli 加合物的合成和抗尿酸盐活性

脲酶是一种金属酶，其活性位点含有两个 Ni（II）离子，可催化尿素水解为氨和二氧化碳。开发有效的脲酶抑制剂不仅对减少农业中的氮损失至关重要，而且还能为利用脲酶作为毒力因子的抗性病原体引起的感染提供替代治疗方法。本研究的重点是合成和研究带有硼酸基团的 Biginelli 加合物的脲酶抑制潜力。Biginelli 加合物结构中的未取代或羟基取代硼酸基增强了对脲酶的抑制活性。生物物理和动力学研究表明，最好的 Biginelli 加合物（4e；IC50 = 132 ± 12 µmol/L）是一种混合抑制剂，与异构抑制剂相比，它对脲酶活性位点的亲和力更高。对接研究证实了 4e 与脲酶活性所必需的残基之间的相互作用，并证明了其通过羰基或硼酸基团的氧原子与镍原子配位的潜力。总之，Biginelli 加合物 4e 作为一种添加剂，在开发增效肥料和/或医疗应用方面显示出巨大的潜力。

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.