Design, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitors

Hamoud, Mohamed M.S.; Pulya, Sravani; Osman, Nermine A.; Bobde, Yamini; Abdel-Fattah, Hanan A.; Ghosh, Balaram; Ghanim, Amany M.

doi:10.1039/d0nj01274b

Cited by 18 publications

(11 citation statements)

References 34 publications

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“…This inhibitory potential against hERG could be minimized to 1.33 µM by applying derivatization strategies from similar studies [93]. Hamoud et al [94] [97]. In contrast to the assumed chelation by the thiazolidinedione moiety as in previous studies [98], docking results suggested chelation via the amide carbonyl.…”

Section: Non-classic Benzamidesmentioning

confidence: 95%

“…This inhibitory potential against hERG could be minimized to 1.33 µM by applying derivatization strategies from similar studies [ 93 ]. Hamoud et al [ 94 ] used the nicotinamide moiety as an alternative ZBG and varied the cap group. They could show that compound 25 was the most potent in the series, showing an inhibitory activity of 4.64 µM against Hela nuclear extract and 690 nM toward HDAC3.…”

Section: Non-classic Benzamidesmentioning

confidence: 99%

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Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Frühauf

Meyer‐Almes

2021

Molecules

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Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.

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Section: Non-classic Benzamidesmentioning

confidence: 95%

Section: Non-classic Benzamidesmentioning

confidence: 99%

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Frühauf

Meyer‐Almes

2021

Molecules

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“…In continuation of our ongoing efforts to design and study HDAC3 specific inhibitors, ,,, in this present study we report N -(2-aminophenyl)-5-(benzylamino)pyrazine-2-carboxamide (PT3), a novel benzamide class, HDAC3 i as a brain penetrant memory enhancer. PT3 has been designed and developed by our group as a novel HDAC3 selective inhibitor and has previously been reported as a lead molecule for its anticancer properties when compared to the standards (Figure ) BG45 and CI994 .…”

Section: Introductionmentioning

confidence: 88%

PT3: A Novel Benzamide Class Histone Deacetylase 3 Inhibitor Improves Learning and Memory in Novel Object Recognition Mouse Model

Pulya

Mahale

Bobde

et al. 2021

ACS Chem. Neurosci.

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The importance of HDAC3 in transcriptional regulation of genes associated with long-term memory is well established. Here, we report a novel HDAC3 inhibitor, PT3, with an excellent blood–brain barrier permeability and ability to enhance long-term memory in mouse model of novel object recognition (NOR). PT3 exhibited higher selectivity for HDAC3 over HDAC1, HDAC6, and HDAC8 compared to the reference compound CI994. PT3 has significant distribution into the brain tissue with C max at 0.5 h and t 1/2 of 2.5 h. Treatment with PT3 significantly improved the discrimination index in C57/BL6 mice in the NOR model. Brain tissue analysis of mice treated with PT3 for NOR test showed significant increase in H3K9 acetylation in hippocampus. Gene expression analysis by RT-qPCR of the hippocampus tissue revealed upregulation of CREB 1, BDNF, TRKB, Nr4a2, c-fos, PKA, GAP 43, PSD 95 and MMP9 expression in mice treated with PT3. Similar to the phenotype observed in the in vivo experiment, we found upregulation of H3K9 acetylation, CREB 1, BDNF, TRKB, Nr4a2, c-fos, PKA, GAP 43 and MMP9 expression in mouse neuronal (N2A) cells treated with PT3. Thus, our preclinical studies identify PT3 as a potential HDAC3 selective inhibitor that crosses the blood–brain barrier and improves the long-term memory formation in C57/BL6 mice. We propose PT3 as a candidate with therapeutic potential to treat age-related memory loss as well as other disorders with declined memory function like Alzheimer’s disease.

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“…Hamoud and co-workers recently designed and synthesized some N -(4-(2-arylidenehydrazine-1-carbonyl) phenyl) nicotinamide derivatives as potent and HDAC3-selective inhibitors. Pyridine being a bioisostere of benzene, the benzamide ZBG group was replaced with the m -pyridyl carboxamide ZBG function.…”

Section: Hdac3-selective Inhibitorsmentioning

confidence: 99%

Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy

2021

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The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.

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Design, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitors

Abstract: The selected nicotinamide-based HDACi displayed selectivity towards HDAC3 over pan HDAC and exhibited potent cytotoxicity against the used cell lines.

Cited by 18 publications

References 34 publications

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

PT3: A Novel Benzamide Class Histone Deacetylase 3 Inhibitor Improves Learning and Memory in Novel Object Recognition Mouse Model

Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy

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