Hydroxamate, a Key Pharmacophore Exhibiting a Wide Range of Biological Activities

Abstract

Naturally occurring hydroxamic acid derivatives are biosynthesized by microorganisms (siderophores) and plants (benzoxazinoids). Recent developments in drug discovery have highlighted the numerous biological and pharmacological properties that the hydroxamic acid function may possess, leading to therapeutic applications. These properties may be explained by its ability to chelate metals via the presence of two oxygen atoms. Their pharmacological activities can be divided into three groups. The first concerns the ability of these hydroxamic acid derivatives to scavenge metals (particularly iron), which leads to antioxidant, antimicrobial and metal detoxification activities. The latter is largely used to treat iron overload in patients. The second group of activities is related to their ability to inhibit metallo-enzymes, which gives them a wide range of pharmacological effects: antimicrobial, anti-inflammatory and antitumor. The third group is linked to the capacity of these compounds to generate nitric oxide, which confers hypotensive activity. However, hydroxamates exhibit relatively low stability in vivo, which can be overcome by the synthesis of appropriately designed analogs. For this purpose, many different strategies have been proposed. In this review, we compare and discuss the various synthetic pathways used to obtain the most complex of them, the N-substituted hydroxamic acids. We conclude that among numerous protocols reported so far, the direct N-substitution of hydroxamic acids, the acylation of the appropriate N-O derivative and the direct oxidation of the corresponding amide allow for the synthesis of a wide range of new biologically active compounds.

WMJ‐8‐B, a novel hydroxamate derivative, induces MDA‐MB‐231 breast cancer cell death via the SHP‐1‐STAT3‐survivin cascade

“…Recently, agents derived from the pharmacophore hydroxamate with diverse biological and pharmacological properties have attracted much attention in the field of drug discovery (Bertrand et al, ). In addition, most HDAC inhibitors have been hydroxamate derivatives.…”

Synthesis and antiproliferative evaluation of novel hydroxypropyl-ferrociphenol derivatives, resulting from the modification of hydroxyl groups

“…As part of this examination, we first chose to examine the influence of its alkyl chain, for example, by replacing the terminal hydroxyl substituent with its classical bioisosteres including chloro-and thiol-to test their influence on cytotoxic activity ( Figure 2). Hydroxamate-based analogues [28] or oxime ether fragments [29][30][31] are widely applied in medicinal chemistry as ubiquitous pharmacophores that display a broad range of biological activity. By combining our hydroxypropyl-ferrociphenol skeleton with some N-substituted hydroxylamine derivatives, we were also able to probe how such substituents influence the lipophilicity and cytotoxicity of these types of molecules.…”

Cesium Carbonate Promoted Direct Arylation of Hydroxylamines and Oximes with Diaryliodonium Salts

“…Introduction of new carbon–heteroatom bonds by direct arylation of hydroxylamine derivatives has received particular interest owing to the potential preparation of useful intermediates and valuable chemicals containing nitrogen–oxygen bonds 1. Notably, N ‐arylhydroxylamines can be converted into protected 2‐hydroxylanilines by either a Bamberger rearrangement or a disproportionation process depending on the reaction conditions employed 2.…”