Synthesis Of Hydroxamic Acids Research Articles

Enzymatic Catalysts for Hydroxamic Acid Formation: A Mini‐Review

AbstractIn recent years, biocatalysts have emerged as crucial tool in organic synthesis, particularly for the production of drug intermediates and precursors, e.g., the synthesis of hydroxamic acids. Traditionally, hydroxamic acids were synthesized using organic chemistry methods. However, with the growing emphasis on sustainable and environment‐friendly practices, the chemical industry has increasingly turned towards green synthesis approaches. The significance of hydroxamic acids in medicinal chemistry has also contributed to the changing trends. Following the approval of certain hydroxamic acids as histone deacetylase (HDAC) inhibitors for cancer treatment by the Food and Drug Administration (US‐FDA), there has been a renewed focus on their synthesis and the development of derivatives with improved properties. As an alternative route, amidases have emerged as promising biocatalysts for hydroxamic acid synthesis through their acyltransferase activity. Recent advancements in the synthesis approaches for hydroxamic acids are reviewed. The biocatalytic routes are explored, emphasizing the use of amidases and their acyltransferase activity. The scope and potential applications of this chemoenzymatic approach in synthesizing various hydroxamic acids and their derivatives are discussed. Such advancements have the potential to revolutionize the production of these important compounds, making the synthesis process more sustainable, efficient, and economically viable.

A Reaction of N-Substituted Succinimides with Hydroxylamine as a Novel Approach to the Synthesis of Hydroxamic Acids

We describe a novel two-step approach for the synthesis of compounds with a hydroxyl-amide group (hydroxamic acids), which are widely known for their biological activity (histone deacetylase inhibitors, matrix metalloproteinases inhibitors and others). The first stage is the synthesis of N-substituted succinimide via the reaction of aromatic amine or carboxylic acid hydrazide with succinic anhydride. The second step involves the imide ring opening reaction by hydroxylamine. For both stages, universal synthetic methods are developed to exclude additional purification procedures for the target compounds. Sixteen hydroxamic acids are synthesized using the developed approach. Most of the compounds are obtained for the first time.

Sunlight‐ or UVA‐Light‐Mediated Synthesis of Hydroxamic Acids from Carboxylic Acids

AbstractThe development of light‐mediated methods for synthetic applications is increasingly attracting high interest. We present herein a new photochemical protocol for the synthesis of hydroxamic acids, which constitute an important class of medicinal agents, mainly due to their anticancer properties. The method is mediated by UVA‐light or sunlight and its key point is the generation of a charge transfer complex by the interaction of 4‐dimethylaminopyridine with a halomethane. Various carboxylic acids were directly coupled with O‐protected hydroxylamines, upon irradiation with either LED 370 nm or solar light. A detailed study of the mechanism was carried out by the employment of direct infusion–high resolution mass spectrometry (DI‐HRMS), providing experimental evidence for the formation of various activated species, which may lead to the desired product. The light‐mediated protocol was applied in the synthesis of the drugs Vorinostat and Bufexamac.

Microwave-assisted synthesis of hydroxamic acid incorporated quinazolin-4[3H]-one derivatives

A series of 3-hydroxy, 3-ethoxy and 3-benzyloxy-2-methylquinazolin-4[3H]-one derivatives were synthesized in one-pot four-component or in a two-step protocol under microwave irradiation. More specifically, anthranilic acids in combination with triethyl-orthoacetate, the corresponding hydroxylamine hydrochloride derivative (NH2OR·HCl, R = H, Et, Bn) and pyridine in AcOH were irradiated in a microwave reactor at 130–160 °C for 0.5–2 h to give the desired 2-methyl quinazolin-4[3H]-one derivatives in moderate to excellent yields. Isolation of the benzoxazinone intermediates via the reaction of the corresponding anthranilic acids with Ac2O and sequential reaction with NH2OR·HCl in AcOH in the presence of Na2CO3 provided an alternative second formation pathway. The scope and the limitations of the procedures are discussed for anthranilic acids in relation to each hydroxylamine derivative, evaluating data obtained from all attempted reactions and HRMS/MS analyses. The two protocols investigate the formation of molecules that consist of a quinazolinone “privileged” structure fragment accompanied by hydroxamic acid as an additional pharmacophore incorporated within the same molecule, in a rigid, compact form. Both pharmacophores may be highly functionalized and serve as useful intermediates in organic, medicinal and material chemistry, giving the profile of a “synthon” to such molecules. The green character of the reaction is qualified due to: a) the use of acetic acid as the green solvent to replace toxic pyridine; b) the quantity of pyridine, which at the one-pot protocol is in molar equivalency to the amine hydrochloride; c) the short reaction time; d) the relatively high yields.

Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex.

Novel amidase catalysed process for the synthesis of vorinostat drug.

Presently, N-hydroxy-N'-phenyloctanediamide (vorinostat) which is an effective histone deacetylase inhibitor, is being synthesized chemically. Hence, present study aims to develop an eco-friendly approach for the synthesis of vorinostat from N'-phenyloctanediamide through biotransformation. Using the amidase of Bacillus smithii IIIMB2907 in time course conversion and organic solvent compatibility, maximum bioconversion was observed at 12h of reaction time and in presence of ethanol, respectively. Potassium phosphate buffer of pH 7·0 supported maximum bioconversion of N'-phenyloctanediamide (10mmoll-1 ) into N-hydroxy-N'- phenyloctanediamide at 40°C. Bench scale study was successfully carried out with 83% yield of purified vorinostat. In this study, an eco-friendly approach for the biotransformation of N'-phenyloctanediamide into vorinostat was developed by using cell free extract of thermophilic strain B. smithii IIIMB2907. Microbial amidase has achieved remarkable attention in the field of biotransformation for the green synthesis of hydroxamic acids. Utilization of amidase from B. smithii IIIMB2907, specifically in the synthesis of vorinostat drug is a foremost attempt in the development a novel process and can also be employed in the synthesis of its derivatives as well.

Methods for Hydroxamic Acid Synthesis.

Substituted hydroxamic acid is one of the most extensively studied pharmacophores because of their ability to chelate biologically important metal ions to modulate various enzymes, such as HDACs, urease, metallopeptidase, and carbonic anhydrase. Syntheses and biological studies of various classes of hydroxamic acid derivatives have been reported in numerous research articles in recent years but this is the first review article dedicated to their synthetic methods and their application for the synthesis of these novel molecules. In this review article, commercially available reagents and preparation of hydroxylamine donating reagents have also been described.

A Facile Synthesis of Hydroxamic Acids of Nα-Protected Amino Acids Employing BDMS, a Study of Their Molecular Docking and Their Antibacterial Activities

Hydroxamic acids have received much attention as biologically active compounds. Synthetic hydroxamic acids enhance the growth of plant sources and improve the soil quality, act as antibiotics, cell...

Photoinduced one-pot synthesis of hydroxamic acids from aldehydes through in-situ generated silver nanoclusters

Hydroxamic acids have attracted significant attention due to their widespread use in applied chemistry. In this report, a modified Angeli–Rimini method has been achieved via the visible light-mediated catalytic transformation of a variety of heterocyclic, aromatic and aliphatic aldehydes 1a–j to their corresponding hydroxamic acids 2a–j in 81–93% yield. The unique ability of vitamin K3 as a photoredox catalyst to expedite the development of completely new reaction mechanisms and to enable the construction of challenging carbon–nitrogen bonds has been investigated. It is shown for the first time that the vitamin K3 and aldehyde are largely responsible for rapid in situ reduction of Ag+ ions to catalytic photoluminescent Ag nanoclusters that possess a bandgap energy of 2.87 eV and are less than 2 nm in size. A mechanism for this reaction has been proposed and is supported by UV–Vis, TEM, ESI/MS, FT-IR, 1H NMR and 13C NMR analyses. The investigated method utilizes readily available reagents and produces the hydroxamic acids in high yields without the formation of side products, making it simple, practical and cost-effective.

Strategies for the Synthesis of Hydroxamic Acids

Background: Hydroxamic acids are a major class of organic compounds. They have a wide variety of pharmacological actions in targeting cancers, cardiovascular diseases, HIV, Alzheimer's disease, Malaria, Allergic diseases. Objective: The present review focuses on the chemistry of conventional and non-conventional routes for the synthesis of hydroxamic acids reported till date. Conclusion: The hydroxamic acids are conventionally synthesized via carboxylic acid and their acid chloride derivatives. However, some other functional groups i.e. aldehyde, amine, amide and alcohol can also be converted to hydroxamate with ease. The solid phase synthesis techniques are also gaining importance for the synthesis of hydroxamic acids and these pathways have opened a wide arena for the synthesis of diverse and complex hydroxamic acids.

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors.

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.

ChemInform Abstract: Photoorganocatalytic One‐Pot Synthesis of Hydroxamic Acids from Aldehydes.

An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat.

Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes.

An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat.

ChemInform Abstract: One‐Pot Synthesis of Hydroxamic Acids from Aldehydes and Hydroxylamine.

A one-pot oxidative transformation of aldehydes into hydroxamic acids by the use of an aqueous solution of hydroxylamine is reported. The methodology gives high yields and makes use of cheap, abundant and easily available reagents.

ChemInform Abstract: A Two‐Step Tandem Reaction to Prepare Hydroxamic Acids Directly from Alcohols.

The first synthesis of hydroxamic acids from alcohols has been developed. Both benzylic and aliphatic alcohols can be tolerated and applied in this reaction. The methodology is economical, environmentally benign and high yielding.

ChemInform Abstract: Ethyl 2‐Cyano‐2‐(4‐nitrophenylsulfonyloxyimino)acetate‐Mediated Lossen Rearrangement: Single‐Pot Racemization‐Free Synthesis of Hydroxamic Acids and Ureas from Carboxylic Acids.

AbstractEthyl 2‐cyano‐2‐(4‐nitrophenylsulfonyloxyimino)acetate (ECN) is employed as a new coupling reagent for the preparation of hydroxamic acids and their subsequent Lossen rearrangement into the corresponding isocyanates.

One‐Pot Synthesis of Hydroxamic Acids from Aldehydes and Hydroxylamine

AbstractA one‐pot oxidative transformation of aldehydes into hydroxamic acids by the use of an aqueous solution of hydroxylamine is reported. The methodology gives high yields and makes use of cheap, abundant and easily available reagents.magnified image

Presence of multiple acyltranferases with diverse substrate specificity in Bacillus smithii strain IITR6b2 and characterization of unique acyltransferase with nicotinamide

Abstract In the present study two acyltransferases, designated as acyltransferase A and acyltransferase B having completely different substrate specificities were observed in Bacillus smithii strain IITR6b2. Acyltransferase A was partially purified while acyltransferase B was purified to homogeneity by a four steps process with a purification fold of 12.1 and 37.5% yield. Acyltransferase A was found to have affinity for only short chain aliphatic amides with maximum activity towards acetamide. In contrast acyltransferase B had a broad substrate spectrum with highest acyltransferase activity for nicotinamide and exhibited significant high acyltransferase to amide hydrolase activity ratio for various amides. Purified acyltransferase B was a monomeric protein with molecular mass of 63 kDa. Circular dichroism spectroscopy showed that acyltransferase B was αβ protein with 39% α-helix, 17% β-sheet and 26% random coils. The optimum temperature and pH of acyltransferase B were 45 °C and 7.0 respectively. Catalytic efficiency of acyltransferase B was relatively high with a Kcat/Kmamide and K cat /Km NH 2 OH of 32.0 mM−1 s−1 and 2.47 mM−1 s−1 respectively. Heavy metals and thiol modifying reagents inhibited acyltransferase activity while DTT caused a 2.2 fold increase in activity. Furthermore, acyltransferase B showed tolerance to many polar and non polar organic solvents (10–30%, v/v) which is promising for the synthesis of hydrophobic hydroxamic acids. This acyltransferase B has been shown to be of potential use for hydroxamic acid synthesis owing to its high ratio of acyltransferase to amide hydrolase activities and its considerable organic solvent compatibility.

Acetamide hydrolyzing activity of Bacillus megaterium F-8 with bioremediation potential: optimization of production and reaction conditions.

Bacillus megaterium F-8 exhibited an intracellular acetamide hydrolyzing activity (AHA) when cultivated in modified nutrient broth with 3% tryptone, 1.5% yeast extract, and 0.5% sodium chloride, at pH 7.2, 45 °C for 24 h. Maximum AHA was recorded in the culture containing 0.1 M of sodium phosphate buffer, (pH 7.5) at 45 °C for 20 min with 0.2 % of acetonitrile and resting cells of B. megaterium F-8 equivalent to 0.2 ml culture broth. This activity was stable up to 55 °C and was completely inactivated at or above 60 °C. Maximum acyl transferase activity (ATA) was recorded in the reaction medium containing 0.1 M of potassium phosphate buffer, (pH 8.0) at 55 °C for 5 min with 0.85 mM of acetamide as acyl donor and hydroxylamine hydrochloride as acyl acceptor and resting cells of B. megaterium F-8 equivalent to 0.94 mg cells (dry weight basis). This activity was stable up to 60 °C and a rapid decline in enzyme activity was recorded above it. Under the optimized conditions, this organism hydrolyzed various nitriles and amides such as propionitrile, propionamide, caprolactam, acetamide, and acrylamide to corresponding acids. Acyl group transfer capability of this organism was used for the production of acetohydroxamic acid. ATA of B. megaterium F-8 showed broad substrate specificity such as for acetamide followed by propionamide, acrylamide, and lactamide. This amide hydrolyzing and amidotransferase activity of B. megaterium F-8 has potential applications in enzymatic synthesis of hydroxamic acids and bioremediation of nitriles and amides contaminated soil and water system.

Ethyl 2-Cyano-2-(4-nitrophenylsulfonyloxyimino)acetate-Mediated Lossen Rearrangement: Single-Pot Racemization-Free Synthesis of Hydroxamic Acids and Ureas from Carboxylic Acids

Ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (4-NBsOXY) mediated Lossen rearrangement and its application for the synthesis of ureas is demonstrated. Required hydroxamic acids for the Lossen rearrangements were synthesized from carboxylic acids using the same reagent. Finally, reaction of an amine with the produced isocyanate resulted in urea. Good yields without racemization were achieved under milder and simpler reaction conditions. Reactions are compatible with common N-protecting groups, such as Boc, Fmoc, Cbz, and benzyl, as well as various OH protecting groups, such as (t)Bu and Bzl. Conversion from carboxylic acid to urea is achieved in one pot. Most importantly, byproducts Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] and 4-nitrobenzenesulfonic acid can be recovered easily and can be recycled to prepare the reagent. Thus, the method is environmentally friendly and cost-effective.