Acyl Hydrazone Research Articles

In Vitro Selection Implicates ROP1 as a Resistance Gene for an Experimental Therapeutic Benzoquinone Acyl Hydrazone in Toxoplasma gondii.

Toxoplasma gondii is a globally distributed apicomplexan parasite and the causative agent of toxoplasmosis in humans. While pharmaceuticals exist to combat acute infection, they can produce serious adverse reactions, demonstrating a need for enhanced therapies. KG8 is a benzoquinone acyl hydrazone chemotype identified from a previous chemical screen for which we previously showed in vitro and in vivo efficacy against T. gondii However, the genetic target and mechanism of action of KG8 remain unknown. To investigate potential targets, we generated resistant T. gondii lines by chemical mutagenesis followed by in vitro selection. Whole-genome sequencing of resistant clones revealed a P207S mutation in the gene encoding rhoptry organelle protein 1 (ROP1) in addition to two lesser resistance-conferring mutations in the genes for rhoptry organelle protein 8 (ROP8) and a putative ADP/ATP carrier protein (TGGT1_237700). Expressing ROP1P207S in parental parasites was sufficient to confer significant (10.3-fold increased half-maximal effective concentration [EC50]) KG8 resistance. After generating a library of mutants carrying hypermutated rop1 alleles followed by KG8 pressure, we sequenced the most resistant clonal isolate (>16.9-fold increased EC50) and found independent recapitulation of the P207S mutation, along with three additional mutations in the same region. We also demonstrate that a rop1 knockout strain is insensitive to KG8. These data implicate ROP1 as a putative resistance gene of KG8. This work further identifies a compound that can be used in future studies to better understand ROP1 function and highlights this novel chemotype as a potential scaffold for the development of improved T. gondii therapeutics.

The remarkable selectivity of the 2-arylquinoline-based acyl hydrazones toward copper salts: exploration of their catalytic applications in the copper catalysed N-arylation of indole derivatives and C1-alkynylation of tetrahydroisoquinolines via the A3 reaction

Different selective 2-arylquinoline-based acyl hydrazones toward copper(i) salts were synthesised, characterized and studied their applicability as metal ligands in diverse chemical transformations.

Reactivity of N-acyl hydrazone probes with the mammalian proteome

Small molecule probes with distinct reactivities are useful tools for the identification and characterization of protein modifications and function. Herein, we show that hydrazone probes with an N-carbamate structural motif react differently from N-carbamates within the human proteome. Mass spectrometry analysis of probe-treated mammalian cell lysates identified several proteins that were covalently modified by the hydrazone probes, including the cytidine deaminase APOBEC3A. We used this enzyme as a model to explore the reactivity of the probes with amino acid residues using LC-MS/MS. Both reactive serine and cysteine residues outside of the enzyme active site were covalently modified. A 1-napthol leaving group provided the most extensive reactivity. These results confirm a unique chemotype for hydrazone probes which can be further optimized to target distinct targets of the human proteome.

Efficient artificial light-harvesting systems based on aggregation-induced emission in supramolecular gels.

Based on a new designed acyl hydrazone gelator (G2), we developed a supramolecular organogel in glycol with two different hydrophobic fluorescent dyes, namely rhodamine B (RhB) and acridine red, as acceptors. Both the G2@gel-RhB and G2@gel-acridine red systems showed high levels of energy-transfer efficiency and high fluorescence quantum yields.

Structure-based linker exploration: Discovery of 1-ethyl-1H-indole analogs as novel ATX inhibitors

Aiming to develop novel ATX inhibitors, an indole-3-carboxylic acid lead Indole-1 was identified through high-throughput screening (HTS) efforts. The Indole-1 analogs 1–7 was firstly prepared which exerted mild activity comparable to Indole-1 (740 nM) in ATX enzyme assay. Further structural modification to identify type IV ATX inhibitors was proceeded through derivatization of the indole-3-carboxylic acid group. Resultantly, compounds 8–17 containing acyl hydrazone linker displayed poor activity (over 3.49 μM). Alternatively, replacing the acylhydrazone linker with urea counterpart by the amide bond reversal principle, the acquired compounds 18–22 achieved obvious improvements with submicromolar activities. Furthermore, with the aim to reducing cLogP, the thiazole ring of 18–22 was altered to the benzamide (23–32) with the urea linker unchanged. Remarkably, the benzamide derivative 24 with 4-hydroxy piperidine fragment was identified which exhibited prominent activity with IC50 value of 2.3 nM. Especially, dedicated molecular docking study was throughout the modification process which qualified 24 as optimal entity in accordance with the ATX inhibitory results.

Synthesis of non-nucleoside anti-viral cyclopropylcarboxacyl hydrazones and initial anti-HSV-1 structure-activity relationship studies

The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported.

Expanding the horizons of antiplatelet therapy. A pilot study of the antiplatelet properties of a new tropane alkaloid

Introduction. The article discusses the search for new and highly effective drugs for the prevention and treatment of cerebrovascular disease. The aim was to examine the effect of the acyl hydrazone tropane derivative on individual platelet aggregation (PA) sensitivity in in vitro studies. Results . We present the results of a pilot study on the effect of a new acyl hydrazone tropane derivative — acyl hydrazone (2,3,4-trimethoxy-N'-(8-methyl-8-azabicyclo [3.2.1.] octane-3-ylidene) benzohydrazide hydrochloride on PA properties in vitro in healthy volunteers and in patients with chronic cerebrovascular disease. Conclusion . The studied compound has a pronounced ability to suppress PA when administered intravenously in vivo in two concentrations, equivalent to doses of 10 and 100 mg/kg, and its effect is superior to the comparator acetylsalicylic acid, which is used in clinical practice as an antiplatelet drug.

Design, synthesis and evaluation of hydrazine and acyl hydrazone derivatives of 5-pyrrolidin-2-one as antifungal agents

Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent – hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the –NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate “fungicide-like” properties and were devoted of cytotoxicity.

PH-Responsive Polymers for Improving the Signal-to-Noise Ratio of Hypoxia PET Imaging with [18 F]Fluoromisonidazole.

To improve the signal-to-noise ratio of hypoxia positron emission tomography (PET) imaging, stimuli-responsive polymers are designed for the delivery of the hypoxia PET tracer fluorine-18 labeled fluoromisonidazole ([18 F]FMISO). Linear poly(N-(2-(hydroxypropyl)methacrylamide)) polymers are functionalized with hydrazide linkers that form pH-sensitive acyl hydrazone bonds after their conjugation to an [18 F]FMISO ketone analogue. The release of the [18 F]FMISO ketone analogue from the polymers is considerably faster at a lower pH and its uptake is significantly higher in cancer cells growing under acidic conditions. Additionally, the retention of the PET tracer is significantly higher in hypoxic cells compared to normoxic cells. The delivery of a PET tracer using stimuli-responsive polymers may be an attractive strategy to improve signal-to-noise ratios in PET imaging.

Spectroscopic and TDDFT investigation of highly selective fluoride sensors by substituted acyl hydrazones.

In this work, we report the synthesis of two receptors for fluoride ions based on acyl hydrazone, such as N'-[(1Z)-1-(4-fluorophenyl)ethylidene]benzohydrazide (R1) and N'-[(1Z)-1-(2-hydroxyphenyl)ethylidene]benzohydrazide (R2). The receptors R1 and R2 were synthesized from the corresponding ketones and benzoic acid hydrazide and characterized spectroscopically by UV-visible, IR and 1HNMR techniques. The response of R1 and R2 towards different anions was studied colourimetrically in acetonitrile. The receptors exhibited a specific response towards fluoride ions. Further studies of 1:1 composition of receptors, R1/R2:fluoride ions by different spectroscopic techniques such as UV-Visible, IR and 1HNMR spectroscopy indicated the participation of -NH proton of the receptors in the sensing action through the hydrogen bonding. To understand the mechanism, Time-Dependent Density Functional Theory (TD-DFT) studies were done using the CAM-B3LYP/6311G++ (3df,2p) with Grimme's D3BJ empirical dispersion basis set. The studies supported the role of hydrogen bonding interaction of -NH and-OH protons of the receptors with the fluoride ions.

Site-Selective and Rewritable Labeling of DNA through Enzymatic, Reversible, and Click Chemistries

Current methods for bioconjugation rely on the introduction of stable linkers that lack the required versatility to perform sequential functionalizations. However, sequential manipulations are an increasing requirement in chemical biology because they can underpin multiple analyses of the same sample to provide a wider understanding of cell behavior. Here, we present a new method to site-selectively write, remove, and rewrite chemical functionality to a biomolecule, DNA in this case. Our method combines the precision and robustness of methyltransferase-directed labeling with the reversibility of acyl hydrazones and the efficiency of click chemistry. Underpinning the method is a new S-adenosyl-l-methionine derivative to site-selectively label DNA with a bifunctional chemical handle containing an acyl hydrazone-linker and a terminal azide. Functional tags are conjugated via the azide and can be removed (i.e., untagged) when needed at the acyl hydrazone via exchange with hydroxyl amine. The formed hydrazide-labeled DNA is a versatile intermediate that can be either rewritten to reset the original chemical handle or covalently reacted with a permanent tag. This ability to write, tag, untag, and permanently tag DNA is exploited to sequentially introduce two fluorescent dyes on DNA. Finally, we demonstrate the potential of the method by developing a protocol to sort labeled DNA using magnetic beads, with subsequent amplification of the sorted DNA sample for further analysis. The presented method opens new avenues for site-selective bioconjugation and should underpin integrative approaches in chemical biology where sequential functionalizations of the same sample are required.

Photodynamic Control of the Chain Length in Supramolecular Polymers: Switching an Intercalator into a Chain Capper.

Supramolecular systems are intrinsically dynamic and sensitive to changes in molecular structure and external conditions. Because of these unique properties, strategies to control polymer length, composition, comonomer sequence, and morphology have to be developed for sufficient control over supramolecular copolymerizations. We designed photoresponsive, mono acyl hydrazone functionalized benzene-1,3,5-tricarboxamide (m-BTA) monomers that play a dual role in the coassembly with achiral alkyl BTAs (a-BTA). In the E isomer form, the chiral m-BTA monomers intercalate into stacks of a-BTA and dictate the chirality of the helices. Photoisomerization to the Z isomer transforms the intercalator into a chain capper, allowing dynamic shortening of chain length in the supramolecular aggregates. We combine optical spectroscopy and light-scattering experiments with theoretical modeling to show the reversible decrease in length when switching from the E to Z isomer of m-BTA in the copolymer with inert a-BTA. With a mass-balance thermodynamic model, we gain additional insights into the composition of copolymers and length distributions of the species over a broad range of concentrations and mixing ratios of a-BTA/m-BTA. Moreover, the model was used to predict the impact of an additive (chain capper and intercalator) on the chain length over a range of concentrations, showing a remarkable amplification of efficiency at high concentrations. By employing a stimuli-responsive comonomer in a mostly inert polymer, we can cooperatively amplify the effect of the switching and obtain photocontrol of polymer length. Moreover, this dynamic decrease in chain length causes a macroscopic gel-to-sol phase transformation of the copolymer gel, although 99.4% of the organogel is inert to the light stimulus.

Synthesis of Isoquinoline Derivatives via Palladium‐Catalyzed C−H/C−N Bond Activation of N‐Acyl Hydrazones with α‐Substituted Vinyl Azides

AbstractA palladium‐catalyzed cyclization of N‐acetyl hydrazones with vinyl azides has been developed. Various substituted isoquinolines, including diverse fused isoquinolines can be prepared via this protocol in moderate to good yields. Mechanistic studies suggest that α‐substituted vinyl azide serves as an internal nitrogen source. Also, C−H bond activation and C−N bond cleavage have been realized using hydrazone as directing group.magnified image

Solid-State Emissive Metallo-Supramolecular Assemblies of Quinoline-Based Acyl Hydrazone.

Development of fluorescence-based sensory materials for metal elements is currently in the mainstream of research due to the simplicity and usability of fluorescence as a method of detection. Herein, we report a novel “bis”-quinoline-based acyl hydrazone—named bQH that could be synthesized by a facile, low-cost method through simple condensation of hydrazide with an aldehyde. This acyl hydrazone showed emissive properties through Zn selective binding, especially in its solid-state, as shown by experiments such as UV–Vis, photoluminescence (PL), nuclear magnetic resonance (NMR), and inductively-coupled plasma-optical emission spectroscopies (ICP-OES), and energy-dispersive X-ray spectroscopy (EDS) mapping. The binding modes in which bQH coordinates to Zn2+ was proved to consist of two modes, 1:1 and 1:2 (bQH:Zn2+), where the binding mode was controlled by the Zn2+ ion content. Under the 1:1 binding mode, bQH-Zn2+ complexes formed a polymeric array through the metallo-supramolecular assembly. The resulting bQH-Zn2+ complex maintained its fluorescence in solid-state and exhibited excellent fluorescence intensity as compared to the previously reported quinoline-based acyl hydrazone derivative (mQH).

Designing of novel zinc(ii) Schiff base complexes having acyl hydrazone linkage: study of phosphatase and anti-cancer activities.

Three asymmetric tridentate acyl hydrazone Schiff base ligands namely L1, L2 and L3 were prepared via condensation of 4-methoxybenzohydrazide with picolinaldehyde, 1-(pyridin-2-yl)ethanone and phenyl(pyridin-2-yl)methanone respectively. Three bio-relevant mononuclear zinc(ii) complexes [Zn(L1)Cl2]·2H2O (1), [Zn(L2)Cl2] (2) and [Zn(L3)Cl2] (3) were synthesized by treatment of zinc(ii) chloride with the corresponding Schiff base ligands and characterised by the usual physicochemical techniques. The solid state structures of complexes 1 and 3 were evaluated by single crystal X-ray analysis. All complexes were able to hydrolyse the P-O bond of the phosphate monoester in 90% (v/v) DMSO-water medium using 4-nitrophenylphosphate (4-NPP) as the model substrate and the trend in their activity is 1≈2 > 3. On considering the highly efficient hydrolysis properties, complexes 1-3 were tested as potential therapeutic agents for cancer using HCT116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and A549 (human non-small lung carcinoma) cells. Complex 2 showed the highest IC50 values for anti-cancer activity towards all three cell lines among the three complexes and complex 3 showed the least activity as observed in the phosphatase activity study. The internucleosomal degradation of DNA during apoptosis can be detected by cell death detection ELISA. DNA fragmentation that leads to cell death was examined and when induced by complex 2 in HepG2 cells a significant level of DNA fragmentation was observed at regular intervals of time.

Condensation of 1,2-dicarbonyl compounds with modified Huisgen zwitterions: synthesis of N-aryl-N-acyl hydrazones.

A phosphine-mediated deoxygenative condensation of 1,2-dicarbonyl compounds such as aroylformates, α-diketones, and isatins with arylazocarboxylates has been developed for a facile synthesis of N-aryl-N-acyl hydrazones in moderate to excellent yields under very mild conditions. Mechanistic investigation based on 31P NMR tracking experiments unveils that the reaction is initiated with the in situ formation of the modified Huisgen zwitterions from arylazocarboxylates and PPh3 and proceeds via a nitrogen to nitrogen ester group migration process. This study also represents the first exploration of the reactivity patterns of the modified Huisgen zwitterions derived from arylazocarboxylates toward electrophiles such as 1,2-dicarbonyl compounds.

Light-induced disruption of an acyl hydrazone link as a novel strategy for drug release and activation: isoniazid as a proof-of-concept case

Photocleavage of an acyl hydrazone bridge was achieved by conjugating isoniazid to a ruthenium(ii) metal complex through the generation of singlet oxygen, which released and activated the anti-tuberculosis pro-drug isoniazid.

BOPAHY: a doubly chelated highly fluorescent pyrrole-acyl hydrazone -BF2 chromophore.

New easily functionalisable and highly fluorescent BOPAHY chromophores are synthesised via a one-pot two-step reaction starting from commercially available pyrrole-2-carbaldehydes and respective acyl hydrazides in the presence of BF3·OEt2. Most importantly, all BOPAHY dyes show excellent photophysical properties with quantum yields up to 0.92. Steady-state spectroscopy and quantum chemical calculations provide a first insight into these promising properties.

Synthesis, characterization and pharmacological activity of Ibuprofen Acyl Hydrazones and their Conversion into 1,3,4-Oxadiazoline Derivatives

This work implicates the synthesis of Ibuprofen Acyl Hydrazones and then Converted into the new 1,3,4-Oxadiazoline derivatives that characterized by proton-NMR, FT.IR and elemental microanalysis (CHN) techniques. The intermediates and final compounds were investigated for their physicochemical properties, including the melting point, color, the yield percent, and thin-layer chromatography performed by using TLC silica gel (60) F254, Merck (Germany), to identify the purity of the products and to know the reaction endpoint. Compounds were monitored by UV light irradiation and the elution by using the following systems:: ethyl acetate: hexane ( 3:7), ethyl acetate, ethanol:dioxan (1:1) and methanol: chloroform (1:9). The study was performed using Swiss albino mice (25-30 g) for the pharmacological activity assessment. Hind edema template of carrageenan used for anti-inflammatory activity assessment and the analgesic activity evaluated using ( writhing induced by acetic acid ) and hot plate method, the results show that all the final compounds present with good anti-inflammatory plus analgesic activities exhibited in the animal model of our experimental work , we observed that the standard compound and the synthesized derivatives substantially reduced carrageenan-induced edema at all-times (2,4,6,24) hours, all chemically synthesized new compounds actually significantly reduced the number of acetic acid writhings induced in mice and finally in hot plate method there is high increase in the reaction time to painful stimulation

One‐pot exchange reaction of acyl hydrazone combined with radical polymerization of styrene derivatives bearing acyl hydrazone moieties

ABSTRACTWe developed a one‐pot reaction combining an exchange reaction of the benzylidene moiety in an acyl hydrazone with styrene radical polymerization. The one‐pot reaction of a styrene derivative bearing a 4‐(dimethylamino)benzylidene acyl hydrazone moiety was conducted in the presence of 4‐cyanobenzaldehyde and pyridinium p‐toluene sulfonate/H2O for the exchange reaction and AIBN as the radical polymerization initiator in N,N‐dimethylformamide at 70 °C for 20 h. The exchange reaction proceeded quantitatively, with the 4‐(dimethylamino)benzylidene acyl hydrazone moiety being exchanged with 4‐(methoxy)benzylidene acyl hydrazone, and polymerization proceeded smoothly to provide the corresponding polymer in 70% yield. Compared to traditional stepwise methods and polymer post‐polymerization modifications, this one‐pot system exhibits distinct advantages for the facile and efficient preparation of various functional polymers. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 2505–2510