Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase

Li, Zai-Shun; Wang, Weimin; Lu, Wei; Niu, Congwei; Li, Yonghong; Li, Zhengming; Wang, Jianguo

doi:10.1016/j.bmcl.2013.05.013

Cited by 43 publications

(17 citation statements)

References 25 publications

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“…Unsymmetrical aromatic disulfides obtained from monothiolated compounds inhibit the SARS-CoV M pro (an important target to fight severe acute respiratory syndrome-associated coronavirus, SARS-CoV) probably by interacting with the catalytic cysteine containing the protease M pro [62]. Li et al reported the synthesis of unsymmetrical aromatic disulfides as novel inhibitors ("herbicides") of the acetohydroxyacid synthase, a plant and microorganism enzyme involved in the biosynthesis of branched-chain amino acids [63]. Reynolds and co-workers published unsymmetrical aryl-alkyl disulfides that selectively inhibit the methicillin-resistant Staphylococcus aureus and Bacillus anthracis [64].…”

Section: Discussionmentioning

confidence: 99%

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Rieux

Goffinont

Coste

et al. 2020

IJMS

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DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Rieux

Goffinont

Coste

et al. 2020

IJMS

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“…In the past of our research, we found that some unsymmetrical aromatic disulfides could inhibit plant AHAS and was useful for herbicide research (Fig. 1E) [21,22].…”

Section: Introductionmentioning

confidence: 90%

“…The target unsymmetrical disulfides were synthesized by the reaction of various substituted 2-mercapto- [1,3,4]oxadiazole, substituted 2-mercapto-thiazole, substituted 2-mercapto-1Himidazole or substituted 2-mercapto-pyrimidine with substituted arenesulfenyl chloride in ethyl ether under very mild condition as reported previously [21,22]. It is a quite straightforward nucleophilic substitution, in which the thiol group in the mercapto compound serves as a nucleophilic reagent and attacks the sulfur atom in the arenesulfenyl chloride.…”

Section: Chemistry Of the Target Compoundsmentioning

confidence: 99%

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Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study

Wang

Bao

Song

et al. 2017

European Journal of Medicinal Chemistry

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The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M. These novel compounds displayed excellent IC data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures.

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“…(a)1,2,3-thiadiazole (b)1,2,5-thiadiazole (c) 1,2,4-thiadiazole and (d) 1,3,4-thiadiazole 7 . Among, 1,3,4-thiadiazoles having more applications and exhibiting potential biological activities like insecticidal 8,9 , fungicidal 10,11 ,herbicidal activity 12 , potent anti-cancer 13,14 ,anti-proliferative activity 15,16 , Antiviral 17 , inhibitors of acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE) 18 , Alzheimer 19,20 , and antimicrobial activities 21 . 1,3,4-thiadiazoles also used in electrical and optical 22 , liquid crystal [24][25][26] , corrosion inhibitors 27 , in dye preparation 28 .…”

Section: Introductionmentioning

confidence: 99%

5-[Substituted]-1, 3, 4-thiadiazol-2-amines: Synthesis, Spectral Characterization, and Evaluation of their DNA interactions

Shivakumara¹,

Krishna²

2019

10.5267/j.ccl

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The presence of heterocyclic moiety in diverse compounds, strongly indicative of the desired effect on physiological activity, and it reflects on efforts to find useful synthetic drugs. In this connection, here reporting the synthesis and characterization of 5-[substituted]-1, 3, 4thiadiazol-2-amines (1-7). All the prepared compounds were characterized by spectroscopic methods viz. 1 H-NMR, 13 C{ 1 H}-NMR, FT-IR, and LC-MS. The results of the DNA binding interactions using absorption and fluorescence spectroscopy reveal that the compounds are avid binders to DNA. A DNA cleavage study with pUC18 DNA using gel electrophoresis indicates the compounds are able to cleave DNA in presence of oxidant H2O2.

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Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase

Cited by 43 publications

References 25 publications

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study

5-[Substituted]-1, 3, 4-thiadiazol-2-amines: Synthesis, Spectral Characterization, and Evaluation of their DNA interactions

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