Aromatic Hydrazones Research Articles

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds.

Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 μM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.

Synthesis, characterization, and comprehensive computational analysis of aromatic hydrazone compounds: Unveiling quantum parameters, evaluating antioxidant activity, and investigating molecular docking interactions

This study presents a synergistic approach encompassing experimental synthesis, computational analysis, and antioxidant activity evaluation of two aromatic hydrazone compounds, namely 4-[(2E)-2-(2-nitrobenzylidene) hydrazinyl] benzoic acid (NBHZ) and 4-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] benzoic acid (HBHZ). Efficient synthesis yielded impressive quantities (70 % and 58 %, respectively), and structural characterization employed IR, UV–Vis, and NMR spectroscopy. Antioxidant potential was assessed using the DPPH free radical scavenging assay, revealing distinct capabilities of NBHZ and HBHZ, each featuring a nitro (NO2) and a hydroxy (OH) group, respectively, at the ortho position. HBHZ exhibited superior efficacy (IC50 = 1.15 μg/mL) compared to NBHZ (IC50 = 2.1 μg/mL) and the standard antioxidant BHT (IC50 = 1.83 μg/mL). Computational analyses using Gaussian 09 at the B3LYP/6–311 G(d,p) level elucidated electronic characteristics, molecular electrostatic potential (MEP), HOMO-LUMO energies, and global reactivity descriptors. VEDA 4 further investigated vibrational behavior and potential energy distribution (PED), topological analyses electron localization function (ELF), localized orbital locator (LOL), average localized ionization energy (ALIE), and reduced density gradient (RDG) were identified to evaluate their interactions. Thermochemical parameters explored antioxidant mechanisms (hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT), and sequential proton loss electron transfer (SPLET)). Molecular docking via iGEMDOCK revealed binding interactions with the target NADPH oxidase. These findings not only provide insights into the compounds' antioxidant potential but also underscore the impact of specific molecular features on their properties. This integrated approach contributes to advancing the understanding of hydrazone compounds, guiding the design of materials with tailored functionalities for applications in oxidative stress mitigation.

Photoactivation of Hydrazones for the Synthesis of Diarylalkanes and Trialkylmethylboronates: The Key Role Played by Soluble Base.

The synthesis of diaryl alkanes and tertiary organoboronates via Barluenga coupling at room temperature occurred via photoactivated conversion of aryl sulfonyl hydrazones to diazo compounds in the presence of soluble bases. The combination of arylsulfonyl hydrazone and a soluble base is necessary to provide a near-UV chromophore. Using aromatic hydrazones and aromatic boronic acids resulted in rapid deboronation because of the instability of dibenzylic boron intermediates. Alkyl hydrazones allowed the isolation of derivatives of the tertiary boronate.

New aromatic hydrazones: Synthesis, structural analysis, DFT study, biological activity, ADME-T properties and in silico evaluation of their inhibition of SAS-CoV-2 main protease

Three new hydrazones namely: (2E)-1-(4-methylphenyl-2-[(thiophen-2-yl)methylidene]hydrazine (HZ-1), (2E)-1-(4-methylphenyl)-2-[(thiophen-3yl)methylidene]hydrazine (HZ-2) and (1E)-1[(furan-2-yl)methylidene]-2-(4methylphenyl)hydrazine (HZ-3) have been synthesized by reacting (4-methylphenyl)hydrazine with three heterocyclic aldehydes: 2-thiophenecarboxaldehyde, 3-thiophenecarboxaldehyde and 2-furaldehyde in ethanol at reflux 78 °C. The structures of these compounds were confirmed by spectroscopic and physicochemical methods such as UV–Vis, IR, melting point, 1H NMR and 13C NMR spectra. Their antioxidant activity was evaluated using DPPH, ABTS, FRAP, CUPRAC and phenanthroline assays. The obtained results indicate that the title molecules exhibit excellent activity better and comparable as standards BHT, BHA and ascorbic acid. Also, the synthesized compounds show a good antibacterial activity against two such: P. aeruginosa and B. subtilis. In addition, the density functional theory (DFT) is used to calculate the optimized molecular structures, electronic and vibrational spectra, reactivity, stability and some quantum chemical parameters of the synthesized molecules. The obtained theoretical results are in good agreement with the experimental results. Finally, in silico predictions of ADME-T and pharmacokinetic parameters indicated that these compounds should have good oral bioavailability. Also, the molecular docking has been used to predict the inhibitory activity of SARS-CoV-2 main protease (Mpro) of the studied hydrazones.

Research Progress on the Biological Activities of Metal Complexes Bearing Polycyclic Aromatic Hydrazones

Due to the abundant and promising biological activities of aromatic hydrazones, it is of great significance to study the biological activities of their metal complexes for the research and development of metal-based drugs. In this review, we focus on the metal complexes of polycyclic aromatic hydrazones, which still do not receive much attention, and summarize the studies related to their biological activities. Although the large number of metal complexes in phenylhydrazone prevent them all from being summarized, the significant value of polycyclic aromatic hydrocarbons themselves (such as naphthalene and anthracene) as pharmacophores are also considered. Therefore, the bioactivities of the metal complexes of naphthylhydrazone and anthrahydrazone are focused on, and the recent research progress on the metal complexes of anthrahydrazone by the authors is also included. In terms of biological activities, these complexes mainly show antibacterial and anticancer activities, along with less bioactivities. The present review demonstrates that the structural design and bioactivities of these complexes are fundamental, which also indicates a certain structure-activity relationship (SAR) in some substructural areas. However, a systematic and comprehensive conclusion of the SAR is still not available, which suggests that more attention should be paid to the bioactivities of the metal complexes of polycyclic aromatic hydrazones since their potential in structural design and biological activity remains to be explored. We hope that this review will attract more researchers to devote their interest and energy into this promising area.

Excited state intramolecular proton transfer and topography of conical intersection of aromatic hydrazone Schiff bases

We investigated the energy landscapes of several aromatic hydrazone Schiff base molecules using the SA-CASSCF and MS-CASPT2 theories. We located the energy-minimized conical intersection (MECI) of the S1/S0 surfaces. Furthermore, we evaluated the dot products of the S1 energy gradient in the Franck-Condon geometry with the gradient difference and the interstate coupling vectors. Additionally, we obtained the topographical parameters of the MECIs. We examined the excited state intramolecular proton transfer (ESIPT) using TD-DFT, which reveal that ESIPT on the S1 surfaces involve very small barriers. Some of the investigated Schiff base compounds are potential photoswitches.

Synthesis and Biological Evaluation of Novel Betulin Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents

A series of novel betulin-28-hydrazone derivatives (7a-7o) were synthesized. All compounds were evaluated for their in vitro cytotoxicities in four human carcinoma cells (HepG2, MCF-7, HCT-116 and A549). Among them, compound 7l displayed the most potent cytotoxicity with an IC50 (concentration of the tested compound that inhibits 50% of cell growth) value of 7.37 ± 0.38 μM against MCF-7 cells. The preliminary cellular mechanism studies indicated that compound 7l could induce MCF-7 cells apoptosis. The above findings indicated that compound 7l may be used as a lead compound for antitumor agents with improved efficacy.

Copper-Catalyzed Conjugate Addition of Carbonyls as Carbanion Equivalent via Hydrazones

Copper-catalyzed conjugate addition is a classic method for forming new carbon-carbon bonds. However, copper has never showed catalytic activity for umpolung carbanions in hydrazone chemistry. Herein, we report a facile conjugate addition of hydrazone catalyzed by readily available copper complexes at room temperature. The employment of mesitylcopper(I) and electron-rich phosphine bidentate ligand is a key factor affecting reactivity. The reaction allows various aromatic hydrazones to react with diverse conjugated compounds to produce 1,4-adducts in yields of about 20 to 99%.

Cd(II) coordination polymer of fumaric acid and pyridyl-hydrazide Schiff base: Structure, photoconductivity and theoretical interpretation

A 2-D coordination polymer, {[Cd4(ppmh)4(fum)4(H2O)4].3H2O}n (CP) (H2fum, fumaric acid; ppmh, N-Pyridin-2-yl-N′-pyridin-4-ylmethylene-hydrazine) has been synthesized and structurally characterized by single-crystal X-Ray diffraction study. The structure shows that the coordination polymer is constituted by fumarato bridging via chelation/bidentate coordination to neighbouring Cd(II) centers. The ligand, ppmh has two terminal pyridyl-N and hydrazino-N binding centers. One of the pyridyl-N and hydrazino-N forms a five-member chelate ring with Cd(II) while other pyridyl-N coordinates to adjacent Cd(II) ion. The 2D CP extended itself to 3D supramolecular array by virtue of π--- π interaction and H-bonding. The optical bandgap of the CP is 3.29 eV which implies semiconducting nature and has been supported by the ground state computational analysis. The electrical conductivity and I-V characteristic have shown that the conductivity is improved upon light irradiation (DC conductivity: dark, 0.87 × 10−3 and light, 2.45 × 10−3 Sm−1) and approves the Schottky Barrier Diode (SBD) feature. The DFT computation and the partial density of states (PDOS) calculation show that the π-character of the aromatic hydrazone ligand dominates the valence and conduction bands with negligible participation of the Cd orbitals.

Hydrazones and their metal complexes: A short review on their biological potentia

Hydrazones belong to complexes are beneficial in different fields for their essential role in the development of a range of stable complexes in the coordination chemistry. Different researchers have reported the various medicinal properties of hydrazones. Hydrazone and its metal complexes are useful for the detection of some organic components from pharmaceutical formulations. These metallic compounds act as a catalyst for conducting various chemical reactions and help in making different chemical complexes that are effective against bacteria, fungi, and many other microbes. Aromatic hydrazone derivatives can measure the concentration of low molecular weight aldehyde and ketone complexes. Hydrazones possess numerous medicinal properties, including antimicrobial, anti-cancer, antidepressant, anti-tubercular, anti-viral, etc. For the new drug discovery, hydrazones/azomethines are considered to be an important class of compound. From molecular biology to pharmaceutical formulation, organic chemistry, new drug development process, the importance of hydrazone and its metal complexes is immense. The present review aims to highlight the reported biological activities related to hydrazones for the last decade.

Preparation and biological assessment of some aromatic hydrazones derived from hydrazides of phenolic acids and aromatic aldehydes

There has been substantial interest over the past many years in the design of novel chemical compounds containing the azomethine group (-NH-N=CH) and exhibiting various medicinal properties such as antibacterial, antiviral, antifungal, and anti-inflammatory activities. Herein, hydrazones were synthesized via the chemical reaction of substituted aromatic hydrazides with various aromatic aldehydes. The obtained products were confirmed using different physical and spectroscopic techniques, such as m.p., IR, 1H-NMR and 13C-NMR. The present study was designed to synthesize different aromatic hydrazones assembled by various combinations of aromatic hydrazides and aromatic benzaldehydes containing different substituents such as hydroxyl and polyhydroxyl groups as key structural features. Thus, incorporating such moieties and simultaneously creating highly-conjugated systems was expected to create novel species to mimic as much as possible natural phenolics, chalcones and stilbenes. Compounds of aromatic hydrazones synthesized in the present study were tested in vitro for their direct and indirect antioxidant activities using different methods such as DPPH, ABTS and FTC. The antioxidant activities of the new compounds ranged from very weak to very high activity. In addition, the inhibition of tyrosinase and cholinesterase by these compounds was tested. The new compounds containing two or three hydroxyl groups attached to aldehyde rings exhibited significantly greater inhibition effects on tyrosinase or cholinesterase activities in comparison to other compounds of the same series containing only one hydroxyl group.

Novel Aminopyrazole Tagged Hydrazones as Anti-Tubercular Agents: Synthesis and Molecular Docking Studies.

Pyrazole derivatives have been reported to possess numerous pharmacological activities viz., anti-inflammatory, antipsychotic, etc. Our group has disclosed that pyrazole benzamides display potent antibacterial and anti-tubercular activities. Synthesis of new pyrazole acetamides which possess hydrazone group to be evaluated for antitubercular activity. The key intermediate 5-aminopyrazole was synthesized with the known procedure, which is then converted into chloroacetamide. This compound than resulted in hydrazine derivative and finally converted into aromatic hydrazones. All the compounds were screened for antitubercular activity. All the synthesized compounds have been characterized by their spectral data obtained and subjected to anti-tubercular activity. Among all the twenty tested compounds, three compounds, 5a5, 5b5 and 5b7 have demonstrated MIC value of 3.12 μg/mL against MTB H37Rv. Docking studies revealed important hydrogen bonding interactions with InhA. Three compounds 5a5, 5b5 and 5b7 were found to be most potent among the series of compounds. Docking studies of compounds explained the presence of hydrogen bonding and π- π stacking interactions with InhA. Further synthesis of more such derivatives with optimized groups would produce compounds with more potent anti-tubercular activity.

Application of Topological Descriptors in QSAR Modeling: Substituted Hydrazones Used As a Model System

Background: QSAR study of p-substituted aromatic hydrazones was performed to estimate the quantitative effects of selected topological descriptors on their antimicrobial activity. None of the hydrazones inhibited the growth of the Aspergillus spp., while the data obtained with regard to the antifungal activity of the compounds against Candida utilis were insufficient to develop reliable statistical QSAR models. Therefore, the investigation was focused on developing QSAR models for predicting the antibacterial activity of the compounds against Bacillus subtilis. Methods: A set of substituted hydrazones were tested for their in vitro growth inhibitory activity against Candida utilis, Bacillus subtilis and Aspergillus niger and the diameter of the inhibition zone (mm) was measured. The inhibitory activity data, determined in μg/mL, were transformed to the negative logarithms of molar MICs (log1/CMIC). Using Marvinsketch software package, 28 topological descriptors were calculated. Statistical parameters, such as R2, Sd, F-test, R2 adj, Q, SPRESS, PSE and Q2, were used to test the quality of the developed two-, three-, four-parametric and higher QSAR models. Results and Conclusion: Statistical evaluation of the data used to test the quality of the obtained QSAR models indicated that the two-parametric model involving the descriptors Atom Count (AC) and Maximal Projection Area (MAPA) was statistically significant when all the statistical parameters were summarized. The two parameters, AC and MAPA, had opposite input in modeling the antimicrobial activity of the selected hydrazones against Bacillus subtilis.

Copper(II) complexes of aroylhydrazones: Preparation and structural characterization

Structures of solid copper complexes with aroylhydrazones obtained from nicotinic acid hydrazide and salicylaldehyde derivatives differing in substituents on the benzene ring were analysed by means of infrared (IR) and Raman spectroscopy. Studied aromatic hydrazones acted as neutral, monoanionic or dianionic tridentate ligands, depending on the tautomer form adopted during the complexation process. Various additional substituents on the salicylaldehyde originated ring were not involved in metal coordination, thus carbonyl/enolic oxygen, azomethine nitrogen and oxygen of the phenolic hydroxyl group were proposed as the coordination sites for the copper(II) ion. In all applied synthesis conditions Cu(II) complexes were obtained in Cu(II)/hydrazone molar ratio of 1/1, except for a hydrazone with nitro group, which did not form a complex with Cu(II) regardless of the synthetic conditions. Vibrational spectra indicated that hydrazone having only ortho-hydroxyl group with respect to the double CN bond as well as a hydrazone with an additional OH group in para-position on the benzene ring, formed monomeric copper(II) complexes including water as a ligand, while hydrazones with meta-substituents (Cl, OCH3) formed binuclear copper complexes, in which two copper(II) ions bridge hydrazone molecules via phenolic oxygen atom. Thermal properties of prepared copper(II) complexes were investigated by means of thermogravimetric analysis.

UV Spectrophotometric Determination of Thermodynamic Dissociation Constants of Some Aromatic Hydrazones in Acid Media

The spectral behavior of some p-nitro-p-substituted benzoylhydrazones in the perchloric acid media was followed, applying the UV spectroscopy. The position of the absorption maximum in the spectra was defined in acidic media and the electronic transitions were discussed, as well (7<pH<1). The equilibrium between neutral and protonated form was investigated in the ethanol-water (V/V, 1:1) solutions. The observed changes in the UV spectra suggested that protonation process took place in one step. The pH region of protonation ranges between 1.4 and 2.9. Using the changes in the UV spectra which appear as a result of the protonation reaction the stoichiometric dissociation constants were determined numerically (pKBH+ = n·pH + logI) and graphically (intercept of the dependence of logI on pH). Thermodynamic dissociation constants were estimated as an intercept of dependence of pKBH+ on square root of the ionic strength. In order to achieve that, measurements were performed at different ionic strengths: 0.1, 0.25 and 0.5 mol/dm3, adjusted with sodium perchlorate. The obtained thermodynamic pKBH+ values ranged between 2.07 and 2.58. In order to predict proton transfer at a given pH, semiempirical methods AM1 and PM3 were applied. The influence of the substituents present in the p-position of the benzene ring on pKBH+ values of investigated hydrazones was discussed, too. Total energy, binding energy, enthalpy of formation, Gibbs energies of formation, atomic charge and proton affinity values were used to predict protonation site in hydrazone molecule. Furthermore, the stability and the proton affinity of the isomers (E and Z) in which hydrazones exist and their protonated forms were defined.

Synthesis and Biological Evaluation of Novel Steroidal 5α,8α-Endoperoxide Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents

Seven new steroidal 5α,8α-endoperoxide derivatives with C-17 aromatic hydrazone side chain were synthesized. Structures of the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometry. Anti-proliferative activities of the synthesized compounds were evaluated in vitro by the MTT method. Among the seven compounds, 5α,8α-epidioxy-17-(4-chloro-benzylidene)-hydrazonoandrost-3β-ol showed the strongest anti-proliferative activity against three human cancer cell lines (MCF-7, HepG2, and SK-Hep1).

AlCl3·6H2O-catalyzed Schiff-base reaction between aryl ketones and aromatic acylhydrazines/hydrazines in water

Schiff-bases have important applications in the field of analysis, biomedicine, as well as material sciences. Hydrazones and acylhydrazones are two representative types of Schiff-bases. In this study, a green synthesis of aromatic hydrazones and acylhydrazones via Schiff-base reaction of aryl ketones and aromatic acylhydrazines/hydrazines had been reported. In the synthesis, water was used as solvent and AlCl3·6H2O was used as catalyst. The reaction is simple, highly efficient, and eco-friendly.

Synthesis, Solvatochromic Performance, pH Sensing, Dyeing Ability, and Antimicrobial Activity of Novel Hydrazone Dyestuffs

New tricyanofuran intramolecular charge transfer dyes comprising the hydrazone group were prepared and fully characterized in order to study their possible solvatochromism, dyeing ability, and antimicrobial activity. The preparation of the hydrazone dyes was achieved in relatively good yields starting from different aromatic amines. The hydrazone functional group was presented via the azo-coupling reaction of the tricyanofuran compound by the properly substituted diazonium chloride. Chemical structures of the prepared hydrazones were confirmed via nuclear magnetic resonance spectroscopy (1H- and 13C-NMR), Fourier-transform infrared spectroscopy (FT-IR), and elemental analysis (C, H, and N). The UV-visible absorption spectra of the produced sensor colorants displayed interesting solvatochromism in solvents with a different polarity, which was found to be affected by the substituents bonded to the aromatic hydrazone moiety. The pH molecular switching was investigated through tuning the intramolecular charge transfer stimulated by the reversible deprotonation/protonation process in acetonitrile solution showing color change from yellow to purple. The produced disperse dyestuffs were employed for dyeing polyester fibers to introduce acceptable color strength and colorfastness properties. Moreover, the dyes verified a weak to moderate antimicrobial activity against some selected pathogens, including S. aureus, E. coli, and Candida albicans.

ANTIMICROBIAL EVALUATION OF SOME HYDRAZONE DERIVATIVES

Hydrazone derivatives represent one of the most active classes of compounds possessing a broad spectrum of biological activity. The use of the hydrazones is due to their anti-inflammatory, antimicrobial, antidepressant, antitumoral, analgesic, antiplatelet, anticonvulsant, antischistosomiasis and antiviral activity. Due to their physiological activity, they are also used in agriculture as herbicides, insecticides, fungicides and plant growth regulators. Furthermore, hydrazone derivatives possessing an azomethine proton (-NH-N=CH-) constitute a significant class of compounds for new drug development in order to synthesize effective agents against microbial activity. Considering these applications some psubstituted aromatic hydrazones were previously synthesized and characterized. In this study a series of aromatic hydrazones were evaluated for their in vitro growth and inhibitory activity against Bacillus subtilis, Aspergillus niger and Candida utilis, using filter paper disc method. Stock solutions of compounds were prepared in DMSO, as inert medium in three different concentration levels: 1, 5 and 10 mg/mL. A control disc using DMSO without any test compound was included and there was no inhibitory activity in those disks. The diameter of zone of inhibition (mm) was measured. Every test was done in triplicate to confirm the findings. The screening results indicate that not all investigated compounds exhibited antimicrobial activities. It can be noted that compounds with N-p-methoxy substitute group showed the greatest inhibitory effect against Bacillus subtilis (max zone of inhibition of 14.3 mm) and Candida utilis (max zone of inhibition of 16 mm). All investigated hydrazones showed no inhibitory effects against Aspergillus niger.

PRACTICAL APPLICATION OF QSAR TECHNIQUE FOR PREDICTION OF BIOLOGICAL ACTIVITY OF SELECTED HYDRAZONES

One important class of organic compounds is hydrazones which find huge application in many scientific areas. They demonstrate fascinating biological activities like as antioxidant, anti-inflammatory, anticonvulsants, antidepressant, anxiolytic, antihypertensive, anticancer, antimicrobial, anti-tuberculosis, and antifungal activity. This wide palette of the useful medical properties has attracted considerable scientific interest for their synthesis. The biological activity and the changes in this activity depend on the substituents present in the hydrazone molecule. The hydrazones can be used in agriculture as herbicides, insecticides, and plant growth stimulants because of their physiological properties. A series of substituted aromatic hydrazones have been synthesized and evaluated for in vitro antimicrobial activity against: Bacillus subtilis. QSAR study was performed to estimate the quantitative effects of the selected descriptors of derivatives on their antibacterial activity. Topological and physicochemical descriptors were calculated for each molecule and a several two-parametric mathematical models have been selected for further discussion. The statistical significance of each model was measured by a few cross-validation parameters (Q, PRESS/SSY; SPRESS; PSE andQ2). Statistical evaluation of the data used to test the quality of the obtained models, indicated that in statistically significant model both parameters AC (Atom count) and MAPA (Maximal projection area) have opposite input to the modeling of biological activity of the selected hydrazones. Following statistical parameters were obtained for this model: R2 = 0.9444; Sd = 0.0097; F-test = 101.9875; R2adj = 0.9352; Q = 100.1858; PRESS/SSY = 0.0564; SPRESS = 0.0098; PSE = 0.0088 and Q2 = 0.9436.