Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

Evgeny Chupakhin,Dmitry Dar’In,Mikhail Krasavin,Olga Bakulina

doi:10.3390/molecules24050864

Evgeny Chupakhin, Dmitry Dar’In + Show 2 more

Open Access

https://doi.org/10.3390/molecules24050864

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Abstract

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.

Highlights

The ability of cyclic hydroxamic acids (N-hydroxylactams) to chelate metal ions in general—and in particular—defines their utility in drug design [1]
One principal avenue in this regard is based on the recognition of the similarity of synthetic cyclic hydroxamic acids to bacterial siderophores—special metabolites excreted by bacteria to scavenge and deliver iron for the microorganism’s nutritional needs [2]
We present the results of these findings and present characterization of compounds with respect to their iron-binding properties, which validates them characterization of compounds with respect to their iron-binding properties, which validates them potential candidates for iron overload disease treatment or the design of siderophore-based constructs characterization of compounds 7 with respect to their iron-binding properties, which validates them as potential potential candidates for iron iron overload overload disease disease treatment treatment or or the the design design of of siderophore-based siderophore-based as for antibiotic candidates delivery. for as potential candidates for iron overload disease treatment or the design of siderophore-based constructs for antibiotic delivery

Summary

Introduction

The ability of cyclic hydroxamic acids (N-hydroxylactams) to chelate metal ions in general—and in particular—defines their utility in drug design [1]. One principal avenue in this regard is based on the recognition of the similarity of synthetic cyclic hydroxamic acids to bacterial siderophores—special metabolites excreted by bacteria to scavenge and deliver iron for the microorganism’s nutritional needs [2]. Conjugating such moieties to antibiotics helps shuttle those inside bacteria and overcome resistance of the latter to the antibacterial agent [3]. Among the existing synthetic methods for hydroxamic acid, intramolecular nucleophilic cyclization onto O-protected acyclic hydroxamic acids [5], nitroso moiety insertion in cyclic ketones [6], and ring-closing methathesis of bis-olefinic hydroxamic acids [7] can be mentioned

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