Design, synthesis, 3D pharmacophore, QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

Abdel-Atty, Mona M.; Farag, Nahla A.; Kassab, Shaymaa E.; Serya, Rabah A. T.; Abouzid, Khaled A. M.

doi:10.1016/j.bioorg.2014.08.006

Cited by 29 publications

(9 citation statements)

References 66 publications

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“…Structure-based strategies have been widely adopted in the past for the design of class I-II HDAC inhibitors due to abundant crystallographic data 27 28 29 30 31 32 33 . To date, no crystallographic information is available for the HDAC6 catalytic pocket, limiting the rational design of new selective inhibitors.…”

mentioning

confidence: 99%

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Goracci

Deschamps

Randazzo

et al. 2016

Sci Rep

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The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.

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confidence: 99%

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Goracci

Deschamps

Randazzo

et al. 2016

Sci Rep

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“…Subsequently, Biginelli product (8 a – o ) was held at reflux with ethyl 2‐chloroacetate in the presence of pyridine to afford the cyclization product 9 a – o . The nitrogen containing aldehydes 10 a – f and 13 a were obtained by nucleophilic displacement of the 4‐fluorobenzaldehyde with the corresponding amines (Supporting Information Scheme S1) . 10 g – i were commercially available.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationship Analysis of Thiazolo[3,2‐a]pyrimidine Derivatives with Anti‐inflammatory Activity in Acute Lung Injury

Chen

Jin

et al. 2017

ChemMedChem

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Acute lung injury (ALI) has a high lethality rate, and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[3,2-a]pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti-inflammatory activities. Structure-activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS-induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2-a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI.

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“…The 2N and the S atoms of compounds 4 and 5 show closer distances to the zinc ion than those of 1 atom; 2.028 Å and 2.012 Å for the 2N atoms of compounds 4 and 5 respectively, and 3.890 Å and 3.889 Å for the S atom of compounds 4 and 5 respectively. This indicates that there is a high possibility for compounds 4 and 5 to coordinate zinc ion [52,53].…”

Section: Docking Studymentioning

confidence: 94%

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

Al-Amily

Mohammed

2019

Sci. Pharm.

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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.

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Design, synthesis, 3D pharmacophore, QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

Cited by 29 publications

References 66 publications

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Design, Synthesis, and Structure–Activity Relationship Analysis of Thiazolo[3,2‐a]pyrimidine Derivatives with Anti‐inflammatory Activity in Acute Lung Injury

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

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