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This paper provides an overview of the synthesis and biological activity of the most representative benzohydroxamic acid-based histone deacetylase inhibitors published to date. Benzohydroxamic acids comprise an important class of HDAC inhibitors, and recently several of these structures have been evaluated in clinical trials for the treatment of a variety of cancers. In this overview, benzohydroxamic acids were divided in four different classes based on their reported selectivity towards zinc-dependent HDACs: a first and major class consists of HDAC6 selective inhibitors, a second class deals with pan-HDAC inhibitors, a third class comprises HDAC8 selective inhibitors and a fourth, minor class includes dual HDAC6/8 selective inhibitors. Through this approach, structure-activity relationships were identified for each class, which could help future researchers in the design and development of novel benzohydroxamic acid-based HDAC inhibitors., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The synthesis of novel isoform-selective HDAC inhibitors is considered to be an important, emerging field in medicinal chemistry. In this paper, the preparation and assessment of thirteen selective HDAC6 inhibitors is disclosed, elaborating on a previously developed thiaheterocyclic Tubathian series. All compounds were evaluated in vitro for their ability to inhibit HDAC6, and a selection of five potent compounds was further screened toward all HDAC isoforms (HDAC1-11). The capability of these Tubathian analogs to inhibit α-tubulin deacetylation was assessed as well, and ADME/Tox data were collected. This thorough SAR evaluation revealed that the oxidized, para-substituted hydroxamic acids can be recognized as valuable lead structures in the pursuit of novel potent and selective HDAC6 inhibitors.

A small library of 3-[(4-hydroxycarbamoylphenyl)aminomethyl]benzothiophenes was prepared and assessed as a novel class of HDAC6 inhibitors, leading to the identification of three representatives as potent and selective HDAC6 inhibitors. Further tests with regard to inflammatory responses indicated that HDAC6 inhibition can be uncoupled from transcriptional inhibition at the level of activated NF-κB, AP-1, and GR.

Eight N-(4-hydroxycarbamoylbenzyl)-1,2,4,9-tetrahydro-3-thia-9-azafluorenes were efficiently prepared as sulfur analogues of Tubastatin A and thus evaluated as new HDAC6 inhibitors. All compounds exhibited potency against HDAC6, and four of them were active in the nanomolar range (IC(50) = 1.9-22 nM). Further analysis revealed that the sulfone derivatives (designated as Tubathians) are superior to their non-oxidized sulfide analogues, and the two most active sulfones showed good to excellent HDAC6 selectivity compared to all other HDAC isoform classes.