scholarly journals Design, synthesis and docking study of acyl thiourea derivatives as possible histone deacetylase inhibitors with a novel zinc binding group

2019 ◽  
Author(s):  
Duraid H Al-Amily ◽  
Mohammed H Mohammed
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Docking Study ◽  
Binding Mode ◽  
Zinc Binding ◽  
Design Synthesis ◽  
Thiourea Derivatives ◽  
Low Cytotoxicity ◽  
New Compounds

Histone deacetylase inhibitors with zinc binding groups often exhibit drawbacks like non-selectivity or toxic effects. Thus, there are continuous efforts to modify the currently available inhibitors or to discover new derivatives to overcome these problems. One approach is to synthesize new compounds with novel zinc binding groups. The present study describes the utilization of acyl thiourea functionality, known to possess the ability to complex with metals, to be a novel zinc binding group incorporated into the designed histone deacetylase inhibitors. N-adipoyl monoanilide thiourea (4) and N-pimeloyl monoanilide thiourea (5) have been synthesized and characterized successfully. They showed good cytotoxicity against cancer cells with low cytotoxicity against normal cells. Their binding mode to the active site of histone deacetylases have been studied by docking study.

scholarly journals Design, Synthesis, and Docking Study of Acyl Thiourea Derivatives as Possible Histone Deacetylase Inhibitors with a Novel Zinc Binding Group

2019 ◽  
Vol 87 (4) ◽  
pp. 28 ◽  
Author(s):  
Duraid H. Al-Amily ◽  
Mohammed Hassan Mohammed
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Docking Study ◽  
Binding Mode ◽  
Zinc Binding ◽  
Thiourea Derivatives ◽  
Normal Human Breast

Histone deacetylase inhibitors with zinc binding groups often exhibit drawbacks like non-selectivity or toxic effects. Thus, there are continuous efforts to modify the currently available inhibitors or to discover new derivatives to overcome these problems. One approach is to synthesize new compounds with novel zinc binding groups. The present study describes the utilization of acyl thiourea functionality, known to possess the ability to complex with metals, to be a novel zinc binding group incorporated into the designed histone deacetylase inhibitors. N-adipoyl monoanilide thiourea (4) and N-pimeloyl monoanilide thiourea (5) have been synthesized and characterized successfully. They showed inhibition of growth of human colon adenocarcinoma and mouse hepatoblastoma cells with low cytotoxic effect against normal human breast cells. Their binding mode to the active site of several histone deacetylases has been studied by docking and the results gave a preliminary indication that they could be successful histone deacetylase inhibitors.

scholarly journals Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 717 ◽  
Author(s):  
Na Zhao ◽  
Feifei Yang ◽  
Lina Han ◽  
Yuhua Qu ◽  
Di Ge ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Immunoblot Analysis ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Human Cancer Cell Lines

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

Novel histone deacetylase inhibitors: design, synthesis, enzyme inhibition, and binding mode study of SAHA-Based non-hydroxamates

2003 ◽  
Vol 13 (24) ◽  
pp. 4321-4326 ◽  
Author(s):  
Takayoshi Suzuki ◽  
Yuki Nagano ◽  
Azusa Matsuura ◽  
Arihiro Kohara ◽  
Shin-ichi Ninomiya ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Enzyme Inhibition ◽  
Histone Deacetylase Inhibitors ◽  
Binding Mode ◽  
Design Synthesis ◽  
Mode Study

scholarly journals Design, Synthesis and Cytotoxicity Study of Primary Amides as Histone Deacetylase Inhibitors

2019 ◽  
Vol 28 (2) ◽  
pp. 151-158
Author(s):  
Duraid Al-Amily ◽  
Mohammed H. Mohammed
Keyword(s):  
Cell Line ◽  
Histone Deacetylase ◽  
Normal Cell ◽  
Histone Deacetylase Inhibitors ◽  
Zinc Binding ◽  
Primary Amide ◽  
Design Synthesis ◽  
Normal Cell Line ◽  
Amide Derivatives ◽  
Binding Type

Primary amide derivatives as histone deacetylase inhibitors (HDACIs) are very rare. This paper describes the synthesis of primary amide derivatives (compounds 6 and 7) that have the requirements to be histone deacetylase inhibitors of the zinc-binding type. Both of them exhibited good cytotoxicity against the tested cancer cell lines with much lower cytotoxicity against normal cell line.

Novel Histone Deacetylase Inhibitors: Design, Synthesis, Enzyme Inhibition, and Binding Mode Study of SAHA-Based Non-Hydroxamates.

ChemInform ◽  
2004 ◽  
Vol 35 (14) ◽  
Author(s):  
Takayoshi Suzuki ◽  
Yuki Nagano ◽  
Azusa Matsuura ◽  
Arihiro Kohara ◽  
Shin-ichi Ninomiya ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Enzyme Inhibition ◽  
Histone Deacetylase Inhibitors ◽  
Binding Mode ◽  
Design Synthesis ◽  
Mode Study

Piroxicam Analogs: Design, Synthesis, Docking Study and Biological Evaluation as Promising Anti-HIV-1 agents

2021 ◽  
Vol 17 ◽  
Author(s):  
Ali Imani ◽  
Sepehr Soleymani ◽  
Rouhollah Vahabpour ◽  
Zahra Hajimahdi ◽  
Afshin Zarghi
Keyword(s):  
Docking Study ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Hiv Integrase ◽  
Active Molecule ◽  
Design Synthesis ◽  
Molecule Docking ◽  
New Compounds ◽  
Anti Hiv ◽  
Hiv 1

Background: Taking the well-known drug, Piroxicam as a lead compound, we designed and synthesized two series of 1,2-benzothiazines 1,1-dioxide derivatives to assay their ability in inhibition of HIV-1 replication in cell culture. Objective: In this study, we describe the synthesis, docking study and biological evaluation of 1,2-benzothiazines 1,1- dioxide derivatives. Results: Most of the new compounds were active in the cell-based anti-HIV-1 assay with EC50 < 50 M. Among them, compounds 7g was found to be the most active molecule. Docking study using 3OYA pdb code on the most active molecule 7g with EC50 values of 10 M showed a similar binding mode to the HIV integrase inhibitors. Conclusion: Since all the compounds showed no remarkable cytotoxicity (CC50> 500 M), the designed scaffold is promising structure for development of new anti-HIV-1 agents.

A New Reactive Ketenaminal: Synthesis, Coupling Reaction, Tautomeric Study, Docking and Antimicrobial Evaluation of the Products

2020 ◽  
Vol 16 (6) ◽  
pp. 761-773
Author(s):  
Huda K. Mahmoud ◽  
Hanadi A. Katouah ◽  
Marwa F. Harras ◽  
Thoraya A. Farghaly
Keyword(s):  
Binding Site ◽  
Antimicrobial Agents ◽  
Coupling Reaction ◽  
Docking Study ◽  
Binding Mode ◽  
Binding Energies ◽  
Simple Method ◽  
Antimicrobial Evaluation ◽  
New Compounds ◽  
Active Methylene

Background: One of the most successful reagents used in the synthesis of the reactive enaminone is DMF-DMA, but it is very expensive with harmful effects on the human health and reacts with special compounds to generate the enaminone such as active methylene centers. Aim: In this article, we synthesized a new ketenaminal by simple method with inexpensive reagents (through desulfurization in diphenylether). Methods: Thus, a novel reactive ketenaminal (enaminone) was synthesized from the desulfurization of 2-((2-(4-chlorophenyl)-2-oxoethyl)thio)-5,7-bis(4-methoxyphenyl)pyrido[2,3-d]pyrimidin- 4(3H)-one with diphenylether. The starting keteneaminal was coupled with diazotized anilines via the known coupling conditions to give a new series of 2-(4-chlorophenyl)-1-(2-(arylhydrazono)-2- oxoethyl)-5,7-bis(4-methoxy-phenyl)pyrido[2,3-d]pyrimidin-4(1H)-ones. Results: The structures of the new compounds were elucidated based on their IR, 1H-NMR, 13CNMR, and Mass spectra. Moreover, the potency of these compounds as antimicrobial agents has been evaluated. The results showed that some of the products have high activity nearly equal to that of the used standard antibiotic. Additionally, the docking study was done to get the binding mode of the synthesized compounds with the binding site of the DHFR enzyme. The results of molecular docking of the synthesized arylhydrazono compounds are able to fit in DHFR binding site with binding energies ranging from -4.989 to -8.178 Kcal/mol. Conclusion: Our goal was achieved in this context by the synthesis of new ketenaminal from inexpensive reagents, which was utilized in the preparation of bioactive arylhydrazone derivatives.

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