Design, synthesis, biological evaluations and in silico studies of (Z)-2-(2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl-alkyl/arylsulfonates as potential α-glucosidase inhibitors

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lalita Dahiya , Jatin Jangra , Sunil Kumar , Rajiv Kumar , Rajnish Kumar , Sandip V. Pawar , Ashok Kumar Yadav
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Abstract

Diabetes mellitus is considered one of the major worldwide health emergencies of the twenty-first century. This work described development, synthesis, and characterization of new (Z)-2-(2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl-alkyl/aryl-sulfonates. Compounds 7j and 7m were shown to be the most potent among the newly developed (Z)-2-(2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl-alkyl/aryl-sulfonates after in vitro testing for α-glucosidase inhibitory activity. Following that, an in-vivo disaccharide loading test was performed on these compounds. From the cytotoxicity studies, the most potent substance (7m) was also founded non-toxic. To investigate the binding mechanism and important interactions of α-glucosidase’s amino acid residues, docking analyses were completed and binding affinities of the synthesised compounds were observed from −7.1 to 9.6 kcal/mol. To determine the binding stability of the α-glucosidase protein with chemicals 7j and 7m, molecular dynamic simulations were employed. In silico research and prediction studies for absorption, distribution, metabolism, and excretion (ADME) were used to identify the “druggable” pharmacokinetic profiles. In this instance, we developed unique (Z)-2-(2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl-alkyl/aryl-sulfonates as α-glucosidase inhibitors.

Abstract Image

(Z)-2-(2,4-二氧噻唑烷-5-酰基)甲基)-2-乙氧基苯基烷基/芳基磺酸盐作为α-葡萄糖苷酶抑制剂的设计、合成、生物学评价和硅研究。
糖尿病被认为是21世纪世界范围内的重大突发卫生事件之一。本文描述了新型(Z)-2-(2,4-二氧噻唑烷-5-酰基)甲基)-2-乙氧基苯基烷基/芳基磺酸盐的开发、合成和表征。体外α-葡萄糖苷酶抑制实验结果表明,化合物7j和7m是新合成的(Z)-2-(2,4-二氧噻唑烷-5-酰基)甲基-2-乙氧基苯基烷基/芳基磺酸盐中抑制α-葡萄糖苷酶活性最强的。随后,对这些化合物进行体内双糖负荷试验。从细胞毒性研究来看,最有效的物质(7m)也是无毒的。为了研究α-葡萄糖苷酶氨基酸残基的结合机制和重要的相互作用,我们完成了对接分析,并在-7.1 ~ 9.6 kcal/mol范围内观察了合成化合物的结合亲和力。为了确定α-葡萄糖苷酶蛋白与化学物质7j和7m的结合稳定性,采用分子动力学模拟。利用计算机研究和预测吸收、分布、代谢和排泄(ADME)的研究来确定“可用药”的药代动力学特征。在这种情况下,我们开发了独特的(Z)-2-(2,4-二氧噻唑烷-5-酰基)甲基)-2-乙氧基苯基烷基/芳基磺酸盐作为α-葡萄糖苷酶抑制剂。
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
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.
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