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Abstract Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R’OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV–visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (Kb) value for the compound is 6.62 × 104 M−1 and 5.40 × 103 M−1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern–Volmer constants for ct-DNA and t-RNA as 9.96 × 104 M−1 and 8.13 × 105 M−1, respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be − 3.741 × 107 and − 5.425 × 108 kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and β-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations.

Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R'OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV–visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (Kb) value for the compound is 6.62 × 104 M−1 and 5.40 × 103 M−1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern–Volmer constants for ct-DNA and t-RNA as 9.96 × 104 M−1 and 8.13 × 105 M−1, respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be − 3.741 × 107 and − 5.425 × 108 kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and β-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations. [ABSTRACT FROM AUTHOR]

Background Molecular hybridization in drug design is proved to be very successful approach to provide new chemical entities with potential activities and desirable physicochemical properties. Histone deacetylases (HDACs) are involved in controlling the behavior and acetylation of histone and non-histone proteins and their inhibition causes block of cell growth, differentiation, changes in gene expression, and death. Consequently, HDAC inhibitors may lead to anticytotoxic activity. An approach of synthesizing hybrid molecules of benzothiazole cross-linked with hydroxamic acid via an amino acid or aminoalkanoic acid was considered. This approach is expected to optimize the anticytotoxic activity of the proposed compounds. Methods Hybrid molecules of benzothiazole cross-linked with hydroxamic acid ( 2A-E) were synthesized and their chemical structures were confirmed by spectral analyses (FT-IR, 1H-NMR and 13C-NMR). These were subjected to molecular docking on HDAC8 (PDB ID: 1T69). Computational methods were employed using the SwissADME server to predict the ADME parameters and other physicochemical properties. The cytotoxicity evaluation was performed using MTT colorimetric assay. Results Hybrids ( 2A-E) recorded lower ΔG ( -6.322 to - 9.46) than Vorinostat (SAHA, -5.375). ΔG is an affinity scoring function (kcal/mol) and is employed to rank the candidate poses as the sum of the electrostatic and Van der Waals energies. Benzothiazole cross-linked with hydroxamic acid by a p-aminobenzoic acid ( 2E) has recorded the lowest docking score of -9.460 and this may refer to the possibility of high inhibitory activity. The hybrids showed no violation from Lipinski’s rule and complied with parameters with low possible passive oral absorption and no penetration into BBB. Hybrid molecules of benzothiazole recorded very interesting results, particularly, 2D and 2E which showed significant and remarkable activity. Conclusions Hybrid molecules of benzothiazole cross-linked with hydroxamic acid recorded very interesting results, particularly, compounds 2D and 2E which showed significant and remarkable activity on lung cancer cell line type A549.

The pollution of water bodies by heavy metal ions has recently become a global concern. In this experiment, a novel chelating resin, D851-6-AHHA, was synthesized by grafting 6-amino-N-hydroxyhexanamide (6-AHHA) onto the (-CH2N-(CH2COOH)2) group of the D851 resin, which contained a hydroxamic acid group, amide group, and some carboxyl groups. This resin was developed for the purpose of removing heavy metal ions, such as Cr(III) and Pb(II), from water. The findings from static adsorption experiments demonstrated the remarkable adsorption effectiveness of D851-6-AHHA resin towards Cr(III) and Pb(II). Specifically, the maximum adsorption capacities for Cr(III) and Pb(II) were determined to be 91.50 mg/g and 611.92 mg/g, respectively. Furthermore, the adsorption kinetics of heavy metal ions by D851-6-AHHA resin followed the quasi-second-order kinetic model, while the adsorption isotherms followed the Langmuir model. These findings suggest that the adsorption process was characterized by monolayer chemisorption. The adsorption mechanism of D851-6-AHHA resin was comprehensively investigated through SEM, XRD, FT-IR, and XPS analyses, revealing a high efficiency of D851-6-AHHA resin in adsorbing Cr(III) and Pb(II). Specifically, the (-C(=O)NHOH) group exhibited a notable affinity for Cr(III) and Pb(II), forming stable multi-elemental ring structures with them. Additionally, dynamic adsorption experiments conducted using fixed-bed setups further validated the effectiveness of D851-6-AHHA resin in removing heavy metal ions from aqueous solutions. In conclusion, the experimental findings underscored the efficacy of D851-6-AHHA resin as a highly efficient adsorbent for remediating water bodies contaminated by heavy metal ions. [ABSTRACT FROM AUTHOR]

Background The influenza virus is a highly contagious respiratory disease that causes seasonal outbreaks and occasionally, unpredictable pandemics with high morbidity and mortality rates. This problem is exacerbated by the lack of drugs with potential antiviral activity against all types of influenza strains, including resistant strains. Therefore, there is an urgent need to develop novel antiviral agents. Methods The synthesis of new oseltamivir carboxamides with amino acids and the subsequent synthesis of hybrid molecules with hydroxamic acid were considered. Two series are presented as series one; oseltamivir carboxamides with L-serine, L-isoleucine, L-phenylalanine, L-tyrosine and series two included hydroxamates of series one. This approach may provide promising candidates with potential anti-influenza activity. The in vitro cytotoxic activity against Madin-Darby Canine Kidney (MDCK), type (NBL-2) - CCL-34 cells using the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to determine the half maximal inhibitory concentrations (IC 50) of the investigated compounds. The percent inhibition of neuraminidase was plotted against concentrations and the IC 50 values were calculated by non-linear logistic curve fitting. Results The compounds were subjected to molecular docking using the GOLD suite (version 5.7.1) to predict the binding affinities for neuraminidase (3CL0). The docking scores are presented as PLP fitness and are comparable to those of oseltamivir. Oseltamivir-Phenylalanine recorded the highest docking score (72.23 kcal/mol), while, oseltamivir acid was recorded (56.24 kcal/mol). The ADMET parameters were generated using the Swiss ADME server to predict successful candidates with reasonable oral absorption and safety margins. All compounds are safer than oseltamivir and their IC 50 values for neuraminidase inhibition were variable. The hybrids showed a lower percentage of viable cells. Oseltamivir-phenylalanine had the highest inhibitory activity against neuraminidase (3.03 μM), when compared with oseltamivir (67.22 μM). Conclusion Oseltamivir-phenylalanine showed remarkable and very significant activity, and the hybrid molecules were surprisingly less effective on neuraminidase than oseltamivir carboxamides.

Copyright of Al-Mustansiriyah Journal for Pharmaceutical Sciences is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Histone deacetylase inhibitors (HDACIs) represent a well-known class of compounds that exhibit potential therapeutic efficacy in a variety of diseases, particularly cancer and neurodegenerative disorders. This article discusses the development of compound 6 as a new HDAC inhibitor. It was designed based on the structure activity relationship (SAR) of the previously reported HDAC inhibitors and the molecular modeling studies. Compound 6 was synthesized, and its structure was verified using different spectroscopic methods. It was biologically evaluated to assess its inhibitory activity against different HDAC isoforms, including HDAC1, 6, and 8. The results showed moderate inhibition against HDAC 1 and HDAC 8 over HDAC 6. It was also evaluated for its antineoplastic activity against the NCI 60 cancer cell line panel. The results revealed inhibitory activity against both the UO-31 renal cancer cell line and the BT-549 breast cancer cell line. Moreover, the Molecular modeling studies revealed favorable binding affinity for the HDAC8 active site. These results suggest that compound 6 can be considered as a promising candidate for the development of new selective class I HDACIs in the future.

This study involved the development of innovative compounds consisting of dipeptide cross-links combined with hydroxamic acid. Our objective was to assess their binding affinities with histone deacetylase 8 (HDAC8) by conducting a docking study, comparing the results with the reference ligand, suberoylanilide hydroxamic acid (SAHA). Docking scores were measured in terms of ΔG (Kcal/mol), and the recorded scores for compounds 2A-D were found to be higher than that of SAHA, with values of 87.36, 80.46, 79.42, and 74.14, respectively. Notably, compound 2A, a dipeptide consisting of L-tryptophyl-L-tyrosine linked to a hydroxamic acid moiety, exhibited the highest docking score of 87.36. This finding suggests that compound 2A may possess the most potent HDAC8 inhibitory activity among the other designed compounds. Furthermore, we utilized the SwissADME server to predict the physicochemical properties and additional ADME parameters for the designed compounds. The analysis revealed that all investigated compounds exhibited a high potential for passive oral absorption and demonstrated no penetration into the blood-brain barrier. Compound 2A, 2B, and 2D exhibited one Lipinski's rule violation each, whereas Compound 2C demonstrated no such violations in all parameters. Additionally, compounds 2A and 2C exhibited potential as P-glycoprotein (P-gp) substrates. SAHA did not exhibit inhibition of any of the cytochrome P450 (CYP) enzymes used in this study, whereas compounds 2B, 2C and 2D displayed possible inhibitory activities. These compelling findings provide encouraging prospects for the future synthesis of the designed compounds and warrant further evaluation through in vitro and in vivo biological studies.

In this paper, using methyl cinnamate as raw material, the new cinnamic hydroxamic acid collector (CIHA) was synthesized by the hydroxylamine method. The collector performance of hydroxamic acid was investigated for scheelite and gangue calcite, and the flotation separation test of scheelite and calcite was carried out with CIHA as the collector. The interaction mechanism between hydroxamic acid and scheelite minerals has also been investigated through zeta potential, Fourier transform infrared spectroscopy (FTIR) experiments, X-ray photoelectron spectroscopy (XPS) experiments, and density functional theory (DFT) calculation. The single mineral flotation test and artificially mixed ore showed that CIHA had an excellent collection effect and selectivity. Zeta potential, FTIR, and XPS showed that CIHA was adsorbed on the scheelite surface by strong chemical adsorption. The active group of CIHA was analyzed through quantum chemical calculation. It was speculated that CO and NO bonds could synthesize a five-membered chelated hydroxamic acid group with Ca element chelate on scheelite surface, changing hydrophobicity and making it more likely to emerge from the pulp.

A novel method for extracting and measuring trace amounts of indium, gallium, and thallium using a synthesized [2]rotaxane hydroxamic acid is proposed. The method involves extracting the elements at specific pH levels using chloroform and measuring them using spectrophotometry and inductively couples plasma atomic emission spectrometry (ICP-AES). The extraction mechanism and the factors that influence the extraction process are also discussed. The method is shown to be effective for measuring these elements in a variety of samples, such as alloys, environmental samples, minerals, water, and biological samples. The sensitivity of this method is enhanced 60 times by ICP-AES measurements, which makes it useful for trace determination of In, Ga, and Tl. [ABSTRACT FROM AUTHOR]

Superparamagnetic iron oxide nanoparticles (SPION) with a "non-fouling" surface represent a versatile group of biocompatible nanomaterials valuable for medical diagnostics, including oncology. In our study we present a synthesis of novel maghemite (γ-Fe2O3) nanoparticles with positive and negative overall surface charge and their coating by copolymer P(HPMA-co-HAO) prepared by RAFT (reversible addition–fragmentation chain-transfer) copolymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with N-[2-(hydroxyamino)-2-oxo-ethyl]-2-methyl-prop-2-enamide (HAO). Coating was realized via hydroxamic acid groups of the HAO comonomer units with a strong affinity to maghemite. Dynamic light scattering (DLS) demonstrated high colloidal stability of the coated particles in a wide pH range, high ionic strength, and the presence of phosphate buffer (PBS) and serum albumin (BSE). Transmission electron microscopy (TEM) images show a narrow size distribution and spheroid shape. Alternative coatings were prepared by copolymerization of HPMA with methyl 2-(2-methylprop-2-enoylamino)acetate (MMA) and further post-polymerization modification with hydroxamic acid groups, carboxylic acid and primary-amino functionalities. Nevertheless, their colloidal stability was worse in comparison with P(HPMA-co-HAO). Additionally, P(HPMA-co-HAO)-coated nanoparticles were subjected to a bio-distribution study in mice. They were cleared from the blood stream by the liver relatively slowly, and their half-life in the liver depended on their charge; nevertheless, both cationic and anionic particles revealed a much shorter metabolic clearance rate than that of commercially available ferucarbotran. [ABSTRACT FROM AUTHOR]

The structure of four hydroxamic acids (HA) that show antifungal activities in complexes with several metals is revealed by single crystal diffraction. The structures of HA with C2, C6, C10, and C12 hydrocarbon chains are reported. The smallest member of the series, N-hydroxyacetamide (HA2), crystallizes in the centrosymmetric space group P21/c while those with longer chain lengths N-hydroxyhexanamide (HA6), N-hydroxydecanamide (HA10), and N-hydroxydodecanamide (HA12) crystallize in the space group P21, and display remarkable packing. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Central South University is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We report the design and synthesis of novel hydroxamic acid-tethered organoselenium (OSe) hybrids. Their antimicrobial and anticancer activities were assessed against different microbes (e.g., Candida albicans (C. albicans), Escherichia coli (E. coli), and Staphylococcus aureus (S. aureus)), as well as liver and breast carcinomas. OSe hybrid 8 showed promising anticancer activity, with IC50 = 7.57 ± 0.5 µM against HepG2 and IC50 = 9.86 ± 0.7 µM against MCF-7 cells. Additionally, OSe compounds 8 and 15 exhibited promising antimicrobial activities, particularly against C. albicans (IA% = 91.7 and 83.3) and S. aureus (IA% = 90.5 and 71.4). The minimum inhibitory concentration (MIC) assay confirmed the potential antimicrobial activity of OSe compound 8. OSe compounds 8 and 16 displayed good antioxidant activities compared to vitamin C in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. These results indicate that hydroxamic acid-based organoselenium hybrids have promising biological activities such as anticancer, antimicrobial, and antioxidant properties, especially compounds 8, 13, 15, and 16, which warrant further studies. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively.

In our previous work, the clinical phase II HDAC inhibitor quisinostat was identified as a promising antimalarial agent through a drug repurposing strategy, but its safety was a matter of concern. Herein, further medicinal chemistry methods were used to identify new chemical entities with greater effectiveness and safety than quisinostat. In total, 38 novel hydroxamic acid derivatives were designed and synthesized, and their in vitro antimalarial activities were systematically investigated. These compounds at nanomolar concentrations showed inhibitory effects on wild-type and drug-resistant Plasmodium falciparum strains in the erythrocyte stage. Among them, compound 30, after oral administration, resulted in complete elimination of parasites in mice infected with Plasmodium yoelii, and also exhibited better safety and metabolic properties than observed in our previous work. Mechanistically, compound 30 upregulated plasmodium histone acetylation, according to western blotting, thus suggesting that it exerts antimalarial effects through inhibition of Plasmodium falciparum HDAC enzymes.

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations. [ABSTRACT FROM AUTHOR]

In this paper, the copolymer (styrene-methyl methacrylate) was prepared by using free radical polymerization for the copolymerization between methyl methacrylate and styrene in an equal molar mixing ratio and using benzoyl peroxide as a starter at a temperature of 70 °C. Then the prepared copolymer was converted to poly hydroxamic acid, and this was done by reacting the copolymer with hydroxylamine hydrochloride at a base medium of = 13 using sodium hydroxide with heat escalation for a period of 70 °C. The nickel ion sorption capacity of the resultant product was evaluated using poly hydroxamic acid and spectroscopic FT-IR. As well as studying the effect of time, temperature, and acidity function on the sorption capacity by chelating poly hydroxamic acid. Where it was shown that the capacity of adsorption increases with increasing time and decreases with increase in temperature mediated by poly hydroxamic acid. The equations of Arrhenius and Vant Hof were used, and from the enthalpy values, it was shown that the reaction was exothermic, and from the negative compression energy values, it was found that the reaction is spontaneous and the type of physical detention is mediated by poly hydroxamic acid.

Copyright of Journal of Central South University is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.

2-Aryl-2-(3-indolyl)acetohydroxamic acids demonstrate promising antitumor activity, but quickly metabolize in vivo via glucuronidation of hydroxamic acid residue. In an attempt to improve their pharmacokinetics, methyl esters were synthesized via a newly developed protocol for chemoselective mono-methylation of hydroxamic acids. The cytotoxicity of these derivatives against the HeLa cell line was evaluated and found to be inferior compared to the parent lead compounds. [ABSTRACT FROM AUTHOR]

The title compound represents the thallium(I) salt of a substituted 1,2,5-oxadiazole, [Tl(C3H3N4O3)]n, with amino- and hydroxamate groups in the 4- and 3- positions of the oxadiazole ring, respectively. In the crystal, the deprotonated hydroxamate group represents an intermediate between the keto/enol tautomers and forms a five-membered chelate ring with the thallium(I) cation. The coordination sphere of the cation is augmented to a distorted disphenoid by two monodentately binding O atoms from two adjacent anions, leading to the formation of zigzag chains extending parallel to the b axis. The cohesion within the chains is supported by π–π stacking [centroid–centroid distance = 3.746 (3) Å] and intermolecular N—H...N hydrogen bonds.

The secondary grafting of acrylic acid and acrylamide onto ultra-high-molecular-weight polyethylene (UHMWPE) fibers was accomplished through 60Co gamma-ray pre-irradiation, and UHMWPE fiber adsorbents containing hydroxamic, amide, and carboxyl groups were prepared through a hydroxamic reaction. The results of scanning electron microscope (SEM), attenuated total internal reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and thermogravimetric analysis (TGA) all showed that acrylamide and acrylic acid were successfully grafted onto the fiber and that the hydroxamic reaction successfully converted the amide group into the hydroxamic group. Evaluation of the heavy metal ion adsorption performance indicated that the adsorption capacities of the UHMWPE fiber adsorbent for Cu(II), Co(II), and Ni(II) could reach 318 mg/g, 165 mg/g, and 140 mg/g, respectively (the adsorption concentration was 500 mg/L for 4 h). In the competitive adsorption of copper-cobalt-nickel mixed heavy metal ions, the removal rates of the copper, cobalt, and nickel ions were 99.5%, 43.5%, and 60.5%, respectively (the initial ion concentrations were all 200 mg/L and the amount of adsorbent used was 3 g/L).

A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dual-functional squaramide-hydroxamic acid conjugates were designed and synthesized. • Compound 16 exhibited potent antiproliferative activity in vitro and anti-tumor efficacy in vivo. • Compound 16 effectively elevated lysosomal pH and reduced the levels of intracellular iron. • Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. • Compound 16 demonstrates a synergistic effect on the homeostasis of anions and iron. Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers. [ABSTRACT FROM AUTHOR]

Abstract Background Hydroxamic acids are currently being used in diverse biological activities. We investigated the effect of hydroxamic acid, synthesized from Cyperus esculentus seeds, on the antioxidant status of the liver, spleen, and kidney of Wistar rats. Methods Twenty male rats were randomly divided into three treatment groups using hydroxamic acid at doses of 5, 15, and 50 mg/kg and a control group using distilled water. Rats were sacrificed 24 h after a seven-day repeated oral dosing. After that, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and the levels of glutathione (GSH) and malondialdehyde (MDA) were investigated in the organs. Results Our data showed that MDA levels remained unaltered in the liver, spleen, and kidney. However, it was found that hydroxamic acid at the dose of 50 mg/kg significantly increased SOD activity but depleted CAT, GPx activities and GSH levels in the liver when compared to the control groups. In splenic tissue, SOD activity and GSH levels were significantly diminished. Contrarily, in the kidney, treatment of rats with 50 mg/kg hydroxamic acid did not affect SOD activity, but GPx activity was increased while GST activity was decreased when compared to the controls. Conclusion Overall, hydroxamic acid may enhance antioxidant enzyme activities in the liver and kidney. However, caution is required at higher doses to forestall oxidative stress in the hepatic and splenic tissues.

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This present study reports some natural products and one hydroxamic acid synthetic compound which were previously reported as matrix metalloproteinase-9 (MMP-9) inhibitors to be evaluated for their inhibition toward severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro). This enzyme is one of the proteins responsible for this coronaviral replication. Two herbal methanolic extracts i.e., Averrhoa carambola leaves and Ageratum conyzoides aerial part demonstrate >50% inhibition at 1000 µg/mL. Interestingly, apigenin, one of flavonoids, demonstrates 92% inhibition at 250 µg/mL (925 µM) as well as hydroxamic acid compound, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH), which shows 69% inhibition at 100 µM. The in vitro results are supported by the docking studies revealing that the binding mode of both compounds is mainly by interacting with GLU166 residue in the hydrophobic pocket of the 3CLpro. Pharmacophore mapping further supported the results by confirming that the in vitro activities of both compounds are due to their pharmacophore features employing hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) and hydrophobic. Gas Chromatography-Mass Spectrometry (GC–MS) analysis reported chromene compounds in Ageratum conyzoides aerial part methanolic extract are potential to be this enzyme inhibitor candidate. These all results reflect their potencies to be SARS-CoV-2 inhibitors through 3CLpro inhibition mechanism.

In this paper, an experimental study of (E)-3-(2,6-dichlorophenyl)-acrylamide and its associated dimer were analysed with molecular docking, DFT and QTAIM approach. To spot, describe, and measure the non-covalent interactions (NCIs) of the atoms in the molecules of the monomer and its dimer, some important topological parameters of the charge densities, ρ(r) acquired from the Bader's QTAIM tool are determined, quantitatively. The bond paths are shown to persist for a range of five types of NCIs such as weak conventional (C-H···Cl) and nonconventional (C-O···C and N-O···Cl), medium (N-H···Cl) and strong O-H···O NCIs revealed by the existence of BCPs (ranging from 1.921 - 3.259 Å). A comprehensive explanation of the spectroscopic data like vibrational, electronic, and NMR spectra is reported along with the NLO, reactivity. Hydroxamic acid exhibited an excellent nonlinear optical activity (β0 = 14.8098 × 10−30). To predict the various reactive sites in the molecule, molecular electrostatic potential diagrams were displayed.

The title compound represents the thallium(I) salt of a substituted 1,2,5-oxadiazole, [Tl(C3H3N4O3)]n, with amino- and hydroxamate groups in the 4- and 3- positions of the oxadiazole ring, respectively. In the crystal, the deprotonated hydroxamate group represents an intermediate between the keto/enol tautomers and forms a five-membered chelate ring with the thallium(I) cation. The coordination sphere of the cation is augmented to a distorted disphenoid by two monodentately binding O atoms from two adjacent anions, leading to the formation of zigzag chains extending parallel to the b axis. The cohesion within the chains is supported by π-π stacking [centroid-centroid distance = 3.746-(3)-Å] and intermolecular N-H···N hydrogen bonds. [ABSTRACT FROM AUTHOR]

Tyrosinase, a metalloenzyme containing a dicopper cofactor, plays a central role in synthesizing melanin from tyrosine. Many studies have aimed to identify small-molecule inhibitors of tyrosinase for pharmaceutical, cosmetic, and agricultural purposes. In this study, we report that hydroxamic acid is a potent metal-binding group for interacting with dicopper atoms, thereby inhibiting tyrosinase. Hydroxamate-containing molecules, including anticancer drugs targeting histone deacetylase, vorinostat and panobinostat, significantly inhibited mushroom tyrosinase, with inhibitory constants in the submicromolar range. Of the tested molecules, benzohydroxamic acid was the most potent. Its inhibitory constant of 7 nM indicates that benzohydroxamic acid is one of the most potent tyrosinase inhibitors. Results from differential scanning fluorimetry revealed that direct binding mediates inhibition. The enzyme kinetics were studied to assess the inhibitory mechanism of the hydroxamate-containing molecules. Experiments with B16F10 cell lysates confirmed that the new inhibitors are inhibitory against mammalian tyrosinase. Docking simulation data revealed intermolecular contacts between hydroxamate-containing molecules and tyrosinase.

A series of novel 5′(7′)-substituted-2′-oxospiro[1,3]dioxolane-2,3′-indoline-based N-hydroxypropenamides were designed, synthesized and evaluated for histone deacetylase (HDAC) inhibition and cytotoxicity. It was found that the compounds in this series displayed potent inhibitory effects against HDAC2 with IC50 values as low as 0.284 μM, almost comparable to that of SAHA (IC50, 0.265 μM), a positive control. In Western blot analysis, these compounds also exhibited noted inhibition toward histone deacetylation and this inhibition was found to correlate well with the cytotoxicity of the compounds in three human cancer cell lines. Docking studies indicated the compounds in this series bound to HDAC2 with high binding affinities (∼−9.8 kcal/mol) compared to SAHA (−7.4 kcal/mol).

Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment.

Background: Hydroxamic acids are currently being used in diverse biological activities. We investigated the effect of hydroxamic acid, synthesized from Cyperus esculentus seeds, on the antioxidant status of the liver, spleen, and kidney of Wistar rats. Methods: Twenty male rats were randomly divided into three treatment groups using hydroxamic acid at doses of 5, 15, and 50 mg/kg and a control group using distilled water. Rats were sacrificed 24 h after a seven-day repeated oral dosing. After that, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and the levels of glutathione (GSH) and malondialdehyde (MDA) were investigated in the organs. Results: Our data showed that MDA levels remained unaltered in the liver, spleen, and kidney. However, it was found that hydroxamic acid at the dose of 50 mg/kg significantly increased SOD activity but depleted CAT, GPx activities and GSH levels in the liver when compared to the control groups. In splenic tissue, SOD activity and GSH levels were significantly diminished. Contrarily, in the kidney, treatment of rats with 50 mg/kg hydroxamic acid did not affect SOD activity, but GPx activity was increased while GST activity was decreased when compared to the controls. Conclusion: Overall, hydroxamic acid may enhance antioxidant enzyme activities in the liver and kidney. However, caution is required at higher doses to forestall oxidative stress in the hepatic and splenic tissues. [ABSTRACT FROM AUTHOR]

SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.

Histone deacetylase (HDAC) enzymes play crucial roles in epigenetic gene expression and are an attractive therapeutic target. Five HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to poor single-agent drug efficacy and side effects associated with a lack of HDAC isoform or complex selectivity. An emerging strategy aiming to address these limitations is the development of bifunctional HDAC therapeutics—single molecules comprising a HDAC inhibitor conjugated to another specificity targeting moiety. This review summarises the recent advancements in novel types of dual-targeting HDAC modulators, including proteolysis-targeting chimeras (PROTACs), with a focus on HDAC isoform and complex selectivity, and the future potential of such bifunctional molecules in achieving enhanced drug efficacy and therapeutic benefits in treating disease.

A novel approach to indolo[3,2-c]isoquinoline and dibenzo[c,h][1,6]naphthyridine tetracyclic systems was discovered based on switchable reduction of 2-methoxy-3-(2-nitrophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid prepared via Castagnoli–Cushman reaction. Reduction with ammonium formate resulted in the expected selective transformation of the nitro group (thus providing access to substituted dibenzo[c,h][1,6]naphthyridine via cyclization and dehydrogenation). However, attempted reduction with sodium sulfide initiated a previously unknown reaction cascade including double reduction, cyclization, and decarboxylation, leading to formation of indolo[3,2-c]isoquinoline polyheterocycle in one synthetic step.

The aim of this paper was to use colorimetric assays for hydroxamic acid to quantify the biodiesel content in diesel and compare it with the traditional method (infrared spectroscopy, using the EN 14078 method). Samples were prepared from B2 to B10 with two kinds of diesel - S500 (red) and S50 (yellow) - to obtain two calibration curves. Through statistical methods it was shown that the slopes of the straight lines obtained for the different types of diesel were the same. Thus, the type of diesel did not influence the results of the colorimetric assay for hydroxamic acid. Real samples collected from gas stations were analyzed by both methods (colorimetry and EN 14078). By applying Student's t-test it was concluded that the methods could be considered statistically equivalent. Therefore, it was confirmed that the colorimetric assay for hydroxamic acid is suitable for detecting and quantifying the content of biodiesel in biodiesel/diesel blends and can also be easily adapted to field analyses.

Abstract Heterogeneous Fenton-like catalyst and its industrial application are increasingly given importance for its non-selective mineralization of organic pollutants in broad pH range. Current study, utilized an aromatic hydroxamic acid derivative 2-hydroxypyridine-N-oxide (HpO), for the construction of iron-Hpo ligand catalyst supported on granular activated carbon (GAC). 8-Hydroxyquinoline and citric acid as non-hydroxamic aromatic and aliphatic Fenton-like catalysts were used for comparative evaluation of the efficiency with targeted catalyst (iron-HpO-GAC). This novel catalyst iron-HpO-GAC exhibits excellent efficiency in Acid Red 88 dye removal in the presence of hydrogen peroxide as oxidant at acidic, basic as well as at neutral conditions. Operational conditions for the catalytic oxidation including temperature, dye concentration, pH and catalyst dosage were systematically investigated and analyzed through kinetic studies. Thermodynamic analysis of the catalytic dye removal revealed that the system could oxidize pollutants faster with less activation energy requirement. Higher level of recyclability and stability of the catalyst with less iron leaching was achieved. Finally, the real time application of the catalyst was investigated through successful repeated treatment for actual industrial wastewater. The phytotoxicity assay (with respect to plant Phaseolus mungo) revealed that the degradation of Acid Red 88 and dye wastewater produced nontoxic metabolites which increases its potential application. This study emphasizes the viability of hydroxamate mediated efficient Fenton-like oxidation as a novel approach in designing economically viable pollutant removal technology. Highlights • HpOFe-GAC exhibited 99.8% of excellent removal efficiency of AR 88 dye. • Operational conditions for catalytic oxidation were systematically investigated. • Achieved higher level of recyclability and stability of the catalyst with less iron leaching. • Displayed a novel approach as viable pollutant removal technology with actual wastewater. • Phytotoxicity assay of dye and wastewater produced nontoxic metabolites by catalyst. [ABSTRACT FROM AUTHOR]