Design, Synthesis, and Pharmacological Evaluation of NovelN-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors

Abstract

This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.

Design, Synthesis, and Pharmacological Evaluation of First‐in‐Class Multitarget N‐Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors

“…The HDAC6 inhibition data reinforced that the 4‐dimethylaminobenzoyl cap group of LASSBio‐1911 ( 4 ) is in a solvent‐exposed region, and modifications did not lead to a major impact on the potency. It is noteworthy that the evaluation of LASSBio‐1911 ( 4 ), which was the positive control, showed a similar IC 50 to that obtained previously …”

“…The corresponding acylhydrazines ( 5 b – 32 b ) were obtained in yields ranging from 45 to 90 %. The key intermediate, 4‐formyl‐ N ‐hydroxybenzamide ( 33 ) was prepared from methyl 4‐formylbenzoate, as previously described . Thus, the NAH derivatives 5 – 32 were prepared through the acid‐catalyzed condensation of acylhydrazines ( 5 b – 32 b ) with 4‐formyl‐ N ‐hydroxybenzamide ( 33 ) in yields ranging from 40 to 88 %.…”

“…[c] Determined using the spectrophotometric method developed by Schneider and co‐workers . [d] IC 50 values and aqueous solubility for LASSBio‐1911 ( 4 ) were extracted from the reference …”

Solid state characterization and theoretical study of non-linear optical properties of a Fluoro-N-Acylhydrazide derivative

“…Chemically, they represent a class of azomethine compounds, which can easily be obtained by the condensation of aldehydes or ketones and acylhydrazines in the presence of an acid catalyst[3,4]. However, the presence of appropriate substituent groups can modify the distribution of molecular electrons leading to various properties, such as antitumor[5,6], antiviral[7], antimicrobia[8] and vasodilatory[9] activity. As part of our research, we have synthesized (E)-4-(3-fluorobenzyloxy)-N'-benzylidenebenzohydrazide, a fluoro- N -Acylhydrazone derivative FBHZ (Fig 1).…”

Modeling zinc‐oxygen coordination in histone deacetylase: A comparison of semiempirical methods performance

“…Our research group has great interest in the design of novel HDAC6‐selective inhibitors . Following the new structural insights given by the determination of the crystallographic structures, this work aims to evaluate how some of the most recent semiempirical methods would treat and represent the complex net of interactions presented in the HDAC crystallographic structures.…”