Search Results (90)

Isoniazid (isonicotinic acid hydrazide, INH) is a key drug used to treat tuberculosis (TB), which continues to be the world’s most lethal infectious disease. Nevertheless, the efficacy of INH has diminished because of the emergence of Mycobacterium tuberculosis (Mtb) strains that are resistant to INH. Our goal in this study was to modify INH to reduce this significant resistance chemically. We synthesized INH-based hydrazones (IP1–IP13) through the reaction of INH with in-house obtained benzaldehydes carrying a piperidine or piperazine ring in refluxing ethanol. Upon confirmation of their proposed structures by various spectral techniques, IP1–IP13 were evaluated for their antimycobacterial capacity against Mtb H37Rv strain and INH-resistant clinical isolates with katG and inhA mutations using the Microplate Alamar Blue Assay (MABA). The compounds were additionally tested for their cytotoxicity. The obtained data indicated that the compounds with moderately increased lipophilicity compared to INH (IP7–IP13) were promising antitubercular drug candidates, exhibiting drug-like properties and negligible cytotoxicity. Out of these, IP11 (N′-(4-(4-cyclohexylpiperazin-1-yl)benzylidene)isonicotinohydrazide) emerged as the most promising derivative, demonstrating the lowest MIC values against all Mtb strains tested. Subsequently, the target molecules were evaluated for their capacity to inhibit enoyl acyl carrier protein reductase (InhA), the main target enzyme of INH. Except for IP11 demonstrating 81% InhA inhibition at a concentration of 50 μM, direct InhA inhibition was shown not to be the primary mechanism responsible for the antitubercular activity of the compounds. The binding mechanism of IP11 to InhA was analyzed through molecular docking and molecular dynamics simulations. Altogether, our research identified a novel approach to modify INH to address the challenges posed by the rising prevalence of drug-resistant Mtb strains. Full article

A novel general approach to cyclic hydrazide–hydrazone compounds with a dihydropyridine-2-one core has been developed, involving annulation of symmetrical aldazines with 3-arylglutaconic anhydrides. This approach provides the benefits of straightforward and catalyst-free procedures, diastereoselectivity, and the ability to switch between two isomeric dihydropyridine-2-one cores based on the reaction temperature. Several post-modifications were performed on the side functional groups and the core to demonstrate the synthetic potential of the resulting products. This approach significantly expands the chemical diversity of medicinally relevant N-functionalized δ-lactams. Full article

The search for new antimicrobial agents is one of the major challenges in contemporary medicinal chemistry due to the global issue of increasing drug resistance. In our efforts to identify chemical structures with antibiotic activity that differ from commonly used antibiotics, we focused our research on (thio)semicarbazides and hydrazones. Guided by literature reports, we designed and synthesized a series of novel semicarbazides, thiosemicarbazides, and hydrazones based on the structure of 4-(morpholino-4-yl)-3-nitrobenzohydrazide. The obtained derivatives were subsequently evaluated in in vitro assays for their activity against reference strains of Gram-positive and Gram-negative bacteria. Among the studied groups of compounds, the semicarbazide derivatives exhibited the highest activity. The most active compound identified in the study was a semicarbazide containing a 4-bromophenyl moiety. This compound showed antibacterial potential against Enterococcus faecalis, with a MIC value of 3.91 µg/mL. Among the thiosemicarbazides, the most active compound contained a 4-trifluoromethylphenyl group, with MIC values against Gram-positive bacterial strains (excluding Staphylococcus aureus) ranging from 31.25 to 62.5 µg/mL. None of the tested hydrazones exhibited antimicrobial activity against the examined bacteria. Additionally, the structures of the new compounds were confirmed by single-crystal X-ray analysis, which enabled the investigation of their properties using advanced quantum chemical calculations. Full article

The increase in drug resistance and the high toxicity of current drugs have inspired the scientific community to develop new drugs for various diseases. Hydrazides have become an attractive functional group to easily obtain a plethora of novel compounds with a broad range of biological activities. This review, which contains studies in the literature from the previous five years, focuses on the synthesis methods and biological applications of hydrazides and their derivatives. Here, the details of the experimental reaction conditions used for the synthesis of hydrazides and their derivatives (hydrazide–hydrazones and heterocycle derivatives) are presented, as well as the purification methods and the biological activity of the synthesized compounds. Full article

Background/Objectives: In order to enhance the biological activity, novel complexes of N-(2-bromo-phenyl)-2-hydroxy-benzamide derivatives and β-cyclodextrin were obtained. Methods: The inclusion complexes were characterized using spectral and thermal analyses. The antimicrobial activity was determined using the disk diffusion agar method, and completed with the minimum inhibitory concentration (MIC) values obtained by the broth microdilution method. The in vitro anti-inflammatory activity was evaluated using the protease inhibition assay. Results: The computed supramolecular architectures of the inclusion complexes showed that the most stable molecular arrangements correspond to the models in which the N-(2-bromo-phenyl)-2-hydroxy-benzamide derivatives are partially included in the cyclodextrin cavity. The antimicrobial screening showed that the compounds were active against Gram-positive bacteria (MIC = 2.5–5.0 mg/mL). Also, the evaluation of the proteinase inhibitory activity showed that the IC₅₀ values of the title compounds (0.04–0.07 mg/mL) were much lower than that of the acetylsalicylic acid (0.4051 ± 0.0026 mg/mL) used as positive control, proving their superior efficiency in inhibiting trypsin activity. Conclusions: The complexation proved to be beneficial for both antimicrobial and anti-inflammatory effects. Full article

A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The ³¹P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential. Full article

A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction and features extensive stacking interactions in the crystal. The compound is weakly toxic to HepG2 cells, with an IC₅₀ exceeding 400 μM for 48 h exposure. QN at 50 μM, with the dose reduction index in the range of 1.9–4.4, potentiated the cytotoxicity of several clinical chemotherapeutic drugs, including doxorubicin and other topoisomerase inhibitors, vincristine, and carboplatin, but not cisplatin or 5-fluorouracil. The calculated ADME parameters predict satisfactory drug-like properties for QN. Full article

The increasing number of antibiotic-resistant pathogens forces us to accelerate the search for new antimicrobial agents. Based on this, we chose to synthesize a library of 1-(2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and evaluate their antibacterial activity against various pathogens. A series of (2-hydroxy-5-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid and its hydrazide derivatives were prepared and identified by the methods of IR, ¹H, and ¹³C NMR spectroscopy and a microanalysis technique. The resulting compounds were evaluated in vitro for their efficacy against the Gram-positive Staphylococcus aureus (ATCC 9144), Listeria monocytogenes (ATCC 7644), and Bacillus cereus (ATCC 11778) bacterial strains as well as the Gram-negative Escherichia coli (ATCC 8739) bacteria. Oxacillin, ampicillin, and cefuroxime were used as control antibiotics. Among the obtained compounds, hydrazone with a 5-nitrothien-2-yl fragment surpassed the control cefuroxime (7.8 μg/mL) against almost all strains tested. Hydrazone with a 5-nitrofuran-2-yl moiety showed a slightly lower but also potent effect on all bacterial strains. Moreover, hydrazone with a benzylidene moiety demonstrated very strong inhibition of S. aureus (3.9 μg/mL) in comparison with the antibacterial drug cefuroxime (7.8 μg/mL). In addition, some of these compounds exhibited remarkable bactericidal properties. In a complete biofilm disruption study, 5-nitrothienylhydrazone showed excellent results in disrupting S. aureus and E. coli biofilms. The test results show the potential of the newly obtained derivatives as a source of antibacterial agents. Therefore, further studies on the molecular optimization of these compounds are necessary for the development of new antibacterial drugs. Full article

Background: A series of novel polysubstituted thiazole derivatives were synthesized, and their antiproliferative properties were evaluated using both 2D and 3D lung cancer models. Methods: The compounds were obtained via esterification, oximation, hydrazinolysis, and condensation reactions. Results: Structure–activity relationship analysis revealed that the antiproliferative activity was structure-dependent. Notably, oxime derivatives 21 and 22, along with carbohydrazides 25 and 26, exhibited low micromolar activity that was significantly greater than that of cisplatin (p < 0.005), a standard chemotherapeutic agent. These compounds demonstrated potent, antiproliferative activity against H69 small-cell lung carcinoma cells, as well as anthracycline-resistant H69AR cells. Moreover, compounds 21, 22, 25, and 26 effectively induced cell death in A549 agarose-based 3D spheroids, further supporting their potential therapeutic application. The in silico studies proposed that compound 22 is able to interact with human SIRT2 and EGFR via conserved amino acid residues. Conclusions: The ability of these thiazole derivatives to target both drug-sensitive and drug-resistant lung cancer models highlights their promise as scaffolds for further optimization and preclinical development. Future studies will focus on structural modifications to enhance potency, selectivity, and pharmacokinetic properties, paving the way for the development of novel thiazole-based antiproliferative agents. Full article

Substantial in vitro experimental data have been produced about the safety, antioxidant, neuro- and hepatoprotective effects of a series of recently synthesized N-pyrrolyl hydrazide-hydrazones (compounds 5, 5a–5g). However, compound activity across multiple assays varies and it is challenging to elucidate the favorable physicochemical characteristics of the studied compounds and guide further lead optimization. The aim of the current study is to apply exploratory data analysis in order to profile the biological effects of the novel hydrazide-hydrazones, gain insights related to their mechanisms of action in the context of in silico predictions and identify key predictor–outcome relationships. We collected a dataset from available in vitro studies of compounds 5, 5a–5g. It included cytotoxicity values, protection against hydrogen peroxide-induced damage in HepG2 and SH-SY5Y cells, two radical scavenging assays and a hemolysis assay across a range of treatment concentrations. SwissADME-based predictions of chemometric and ADME parameters and pro-oxidant enzyme docking data were generated to provide context for the interpretation of in vitro outcome patterns and identify causal relationships. Multiple factor analysis (MFA), followed by hierarchical clustering on principal components (HCPC), was applied to profile compounds’ biological behavior. This revealed that differences in the number of H-bond donors, in the permeability coefficient and in the docking scores to two pro-oxidant enzymes could aid in explaining the effects of compounds with similar in vitro profiles. HCPC differentiated 5a as mostly neuroprotective, 5 and 5d as hepatoprotective radical scavengers, 5g with higher docking affinity to 5-lipoxygenase (5-LOX) and myeloperoxidase (MPO) and 5b, 5c and 5f as having less H-bond donors and variable in vitro activity. The consensus application of three variable selection approaches based on standard lasso regression, robust penalized regression and random forest confirmed the relationships between some in vitro outcomes and LogP, pan-assay interference (PAINS) alerts, 5-LOX allosteric site docking and H-bond donor numbers. The exploratory analysis of the combined in vitro and in silico dataset provides useful insights which could help explain the major drivers behind the experimental results. It can be informative in the design of new, improved members of the series of novel N-pyrrolyl hydrazide-hydrazones with better neuroprotective potential and less side effects. Full article

A new water-soluble not-colored antioxidant (Z)-N′-(4-(3,4-dihydroxyphenyl)-3-ethylthiazol-2(3H)-ylidene)-4-hydroxybenzohydrazide hydrochloride (DHTH) was obtained and characterized. The interaction between DHTH and β-CD was studied by experimental thermodynamic methods such as isothermal titration calorimetry (ITC) and ¹H NMR spectroscopy and confirmed by in silico calculations. Thermodynamic data indicated that the inclusion process is driven by enthalpy, predominantly as a result of the guest–host hydrophobic interactions. ¹H NMR measurements were applied to study the interaction with β-CD by changing the studied compound concentration in the solution. UV-vis titration and in vitro antiradical assay were performed, to study the antioxidant activity of DHTH, free and included in β-CD. A molecular docking study added supplementary insight to the experimental analyses regarding the binding conformation of the new polyphenolic compound to β-CD. Full article

Hydrazones, characterized by their C=N–NH functional group, are promising candidates in medicinal chemistry due to their ability to interact with biological targets. This study evaluated the anti-inflammatory and analgesic properties of N-pyrrolylcarbohydrazide (1) and four pyrrole hydrazone derivatives (1A–D) in male Wistar rats (6 weeks old). Anti-inflammatory activity was assessed using a carrageenan-induced paw edema model, while formalin, tail flick, and paw withdrawal tests evaluated analgesia. Compound 1 exhibited dose-dependent anti-inflammatory activity. At 20 mg/kg, significant edema reductions were observed at the 2nd (p = 0.035) and 3rd hours (p = 0.022), while at 40 mg/kg, reductions remained significant at the 2nd (p = 0.008) and 3rd hours (p = 0.046). Compound 1A showed pronounced effects at 20 mg/kg at the 2nd (p = 0.005), 3rd (p < 0.001), and 4th hours (p = 0.004). Other compounds demonstrated minimal or no activity. Analgesic evaluation revealed that at 40 mg/kg, compound 1 significantly reduced paw-licking time in the second phase (p = 0.038). Compounds 1B, 1C, and 1D exhibited transient effects in the first phase only (p < 0.05). Compound 1A lacked significant analgesic activity. The findings suggest that structural modifications may enhance efficacy for broader therapeutic applications. Full article

Microwave-assisted synthesis was applied to obtain fifteen hydrazide-hydrazones of phenylacetic acid. The chemical structure of the synthesized compounds was confirmed on the basis of the analysis of the IR, ¹H NMR and ¹³C NMR spectra. Experimental logP values for all obtained acylhydrazones were established with the use of chromatographic methods. The synthesized compounds were tested for potential antimicrobial activity in in vitro conditions against a panel of microorganisms, which included eight strains of Gram-positive bacteria and six strains of Gram-negative bacteria as well as six strains of yeasts belonging to Candida spp. The assays we performed revealed significant antibacterial activity of obtained hydrazide-hydrazones of phenylacetic acid. Some of the tested compounds possessed much higher activity than that of reference antimicrobial agents towards Gram-positive bacterial strains. It is also worth mentioning that some of synthesized compounds possessed significant activity towards MRSA strain—methicillin-resistant Staphylococcus aureus ATCC 43300 and MSSA strain—methicillin susceptible Staphylococcus aureus ATCC 6538 and ATCC 29213. Full article

The synthetic availability and wide range of biological activity of hydrazides and hydrazones make them attractive subjects for investigation. In this study, we focused on synthesis of 2-methyl-5-nitro-6-phenylnicotinohydrazide-based hydrazones derived from the corresponding substituted aldehydes. The structure of the obtained compounds was studied using NMR spectroscopy and DFT calculations. After repeated recrystallization, all the synthesized compounds remained as mixtures of isomers. As a result of a detailed analysis, we found that the duplication and bifurcation of signals in the ¹H NMR spectra for some atoms is a consequence of the existence of four isomers, namely Z-I, Z-II, E-I and E-II. Duplicate proton signals with a chemical shift difference of 0.1–0.2 ppm and in a ratio of about 2:1 were noticed in the experimental data. By modeling the structures of individual configurations and conformations, Gibbs free energy values were obtained, which allowed us to estimate the approximate content of rotamers for the E-isomer equal to 3:2, which coincided with experimental data. We also tested the antibacterial and antifungal activity of the synthesized compounds. Full article

This study examines the influence of ligand design on the structural, optical, and electrical properties of copper-based coordination complexes. Ligands H₂L¹ and H₂L² were synthesized via the reaction of 5-nitrosalicylaldehyde with 2-hydroxy- or 4-hydroxybenzhydrazide. H₄L³ was obtained from the reaction of carbohydrazide and salicylaldehyde, while H₄L⁴ was prepared by condensing 4-methoxysalicylaldehyde with thiocarbohydrazide. The research focuses on two key design elements: (1) the effect of hydroxyl group positioning on the aroyl ring in hydrazide ligands (H₂L¹ vs. H₂L²) and (2) the impact of carbonyl versus thiocarbonyl groups and aldehyde substituents in hydrazone ligands (H₄L³ vs. H₄L⁴). The resulting complexes, [Cu₂(L¹)₂], [Cu₂(L²)₂(MeOH)₃], [Cu₂(L³)(H₂O)₂], and [Cu₂(L⁴)(H₂O)₂], were synthesized and characterized using attenuated total reflectance infrared (IR-ATR) spectroscopy, thermogravimetric analysis (TG), and UV-Vis diffuse reflectance spectroscopy. Their electrical properties were investigated using solid-state impedance spectroscopy (IS). The crystal and molecular structure of the complex [Cu₂(L²)₂(MeOH)₃]∙MeOH was determined by single-crystal X-ray diffraction (SCXRD). This study underscores the pivotal role of ligand modifications in modulating the functional properties of coordination complexes, offering valuable insights for the advancement of materials chemistry. Full article