Search Results (504)

Background/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a–m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a–m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1–5e and 4BDS–5i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD/RMSF analysis and contact-persistence profiling. Predicted ADME/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (K_I = 20.86 ± 1.61 nM) compared with THA (K_I = 164.40 ± 20.84 nM). For BChE, the K_I values ranged from 31.21 to 87.07 nM and exceeded the reference compound’s activity. MD trajectories supported stable binding in both systems (10–100 ns mean backbone RMSD: 2.21 ± 0.17 Å for 7XN1–5e; 1.89 ± 0.11 Å for 4BDS–5i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e/5g/5h/5i; nephrotoxicity for 5f/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications. Full article

Objective: Based on our previous findings, we designed new molecules by extending functionalized pyrazole derivatives containing iodine atoms, which are linked via an amino bond to halogen-substituted phenyl groups. In addition, these newly developed pyrazole compounds exhibit anti-tumor, antibacterial, and anti-biofilm activities. Methods: Three new series of pyrazole compounds were designed. Fifteen novel pyrazole derivatives, distributed across three series (4a–d, 5a–d, and 6a–g), were synthesized and structurally characterized by ¹H-NMR, ¹³C-NMR, FTIR, UV-Vis spectroscopy, and elemental analysis. Results: Among them, compound 4c, which exhibited notable anti-tumor activity, crystallized in a monoclinic system and was further analyzed via single-crystal X-ray diffraction. All synthesized compounds were evaluated in vitro on NCTC normal fibroblast cells and HEp-2 tumor epithelial cells. Compound 4c demonstrated significant anti-tumor activity while displaying no cytotoxic effects on normal cells. The antibacterial and anti-biofilm activities of the compounds were also assessed against four bacterial strains. Compounds 5a and 5c exhibited the highest antibacterial activity against Staphylococcus aureus ATCC 25923, both with a minimum inhibitory concentration (MIC) of 0.023 μg/mL. Additionally, compounds 4a, 5a, 6a, 6e, and 6f showed the strongest anti-biofilm effects, each presenting a minimum biofilm inhibition concentration (MBIC) of 0.023 μg/mL. ADME and ADMET in silico predictions indicated that all compounds exhibit generally favorable, drug-like physicochemical properties. Conclusions: The study reinforces the applicability of these compounds as promising anticancer, antibacterial, and anti-biofilm drugs. Full article

Background: 8-Quinolinol and its derivatives are drawing significant attention across various disciplines due to their remarkable versatility. These compounds are well-known for their exceptional chelating ability, forming stable metal complexes via their nitrogen and oxygen electron donor atoms. This main characteristic determines their broad utility. Biological activity can also be explained by the chelating capacity, which allows 8-quinolinol to bind to essential metal ions such as Fe, Zn, Cu, and others. This chelation disrupts metal-dependent biological processes in target cells or organisms, leading to a range of effects, including antimicrobial, anticancer, antifungal, and neuroprotective activities. On the other hand, the biological activity of pyrazole derivatives is attributed to their heterocyclic structure, which allows for interactions with biological targets that can lead to enzyme inhibition, receptor antagonism, radical scavenging, and other effects. Objective: This work aimed to synthesize and characterize novel diazene compounds derived from 8-quinolinol or 2-methyl-8-quinolinol and pyrazole amines, and to evaluate their antimicrobial and anticancer activities. Methods: The compounds have been synthesized by coupling diazonium salts obtained from the diazotization of heterocyclic amines with 8-quinolinol and its derivative, 2-methyl-8-quinolinol. The careful selection of reaction conditions enabled the synthesis of high-purity products. The compounds were characterized by 1D and 2D NMR, FT-IR spectroscopy, UV-Vis spectroscopy, and LC-HRMS analysis. The biological activity of the newly synthesized compounds was evaluated following the protocols of EU-OPENSCREEN, a European Research Infrastructure Consortium (ERIC) initiative dedicated to supporting early drug discovery. Results: By combining diazonium salts obtained from 3-methyl-1H-pyrazol-5-amine and ethyl 5-amino-3-methyl-1H-pyrazole-4-carboxylate with the aforementioned coupling agents, four novel 8-quinolinol derivatives were synthesized. The further hydrolysis of the ethoxy carbonyl functional group allowed its conversion to a carboxylic functional group, thus expanding the series of new compounds to six members. Several compounds from the series have proven to be biologically active against several human pathogenic microorganisms and the Hep-G2 cancer cell line. Conclusions: The combination of two well-known biologically active scaffolds through a classic diazo coupling reaction allowed the synthesis of novel biologically active compounds, which showed promising results as possible antifungal and anticancer agents. These results represent a foundation for future studies, which will include a broader biological screening and in vivo studies. Full article

Fused-bicyclic heteroaromatic cores are a common framework in drugs and other biologically active compounds. Those containing azine rings are widely used in drug discovery campaigns. Although these cores are very common, C–H functionalization of their azine moieties remains challenging, especially in annulation reactions. Therefore, this review highlights the progress made over the years in C–H annulation reactions that have produced these essential 6,5-fused bicyclic heteroaromatic cores for drug discovery. For that, the review was divided according to the five-membered rings moiety (pyrrole, pyrazole, imidazole, furan, thiophen, and thiazole) fused to different azines (pyridine, pyrazine, pyridazine, pyrimidine, and triazine). Although some important advances have been made over the years, there remains a need for research in synthetic methodology to expand the use of these heteroaromatic cores in biologically active compounds. Full article

Antibiotic resistance is an increasing concern in modern healthcare. Therefore, it is important to identify novel antimicrobial agents and new molecular targets for such compounds. Here, we describe the identification of an N-pyridylpyrazolone derivative, 4-(2-aminoethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one dihydrochloride (compound 1), which is effective against Gram-positive and Gram-negative bacteria and inhibits the enzymatic activity of Escherichia coli L-threonine dehydrogenase (TDH). To characterize its interaction with compound 1, TDH was overexpressed in E. coli. The recombinant enzyme was shown to exist in dilute solution in equilibrium between dimeric and tetrameric forms, with a K_d value for the dimer/tetramer transition of 3 ± 1 nM, and to bind L-threonine cooperatively with a Hill coefficient of 1.4. Compound 1 acted as a partial mixed inhibitor of TDH with an EC₅₀ value of 47 ± 16 µM and did not affect the equilibrium between oligomeric states. Altogether, these findings identify compound 1 as a promising starting point for the development of novel antibiotics and as a tool compound for studying the functional properties of TDH. Full article

The synthesis of novel pyrazole derivatives (SPDs) and their evaluation for antibacterial potential against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Streptococcus pneumoniae (S. pneumoniae) was developed herein. These compounds were obtained via a microwave-assisted eco-friendly multicomponent reaction (MCR) and were characterized for structural confirmation using ¹H NMR, ¹³C NMR, 2D experiments, TOF-MS, and FTIR spectrometry. Antibacterial activity, as measured by minimum inhibitory concentrations (MICs) of SPDs, ranged between 0.212 and 2.50 mg/mL against S. aureus, S. pneumoniae, P. aeruginosa, and E. coli. Compound 4e was the most potent against S. pneumoniae, with an MIC value of 0.0156 mg/mL compared with Amoxicillin’s MIC value of 0.0306 mg/mL. Thus, compound 4e was observed as a potential lead candidate against S. pneumoniae. Further corroboration by molecular docking at the active site of the key penicillin-binding protein (PBP) revealed that the most potent compounds against each organism showed comparable docking scores to those of amoxicillin. In addition, a pharmacokinetics study showed that synthesized SPDs were predicted to be orally bioavailable and non-inhibitors of cytochrome 3A4 and belong to drug classes 4 and 6. Hence, they were suitable for drug development and warrant further studies such as in vitro assays, in silico modeling, DFT studies, and machine learning for drug design. Full article

Deep Eutectic Solvents (DESs) have emerged as promising candidates to replace conventional organic solvents in various technological applications due to their low vapor pressure, non-flammability, and ease of preparation at low costs. In particular, Type IV DESs, which are composed of metal salts and hydrogen bond donors, are possible replacements for lithium-ion battery electrolytes. In this study, we investigate the molecular dynamics of solvents of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and pyrazole (PYR) at varying LiTFSI:PYR molar ratios (1:2, 1:3, 1:4, 1:5) using Nuclear Magnetic Resonance Dispersion (NMRD) and Pulsed Field Gradient (PFG) Nuclear Magnetic Resonance (NMR). PFG NMR reveals composition-dependent diffusion trends, while NMRD provides molecular-level insights into the longitudinal relaxation rate (R₁ = 1/T₁). Notably, the LiTFSI:PYR (1:2) sample shows distinct behavior across both techniques, exhibiting enhanced relaxation rates and lower self-diffusion for ¹H compared to the other nuclei (¹⁹F and ⁷Li), suggestive of stronger and more efficient Li⁺–pyrazole interactions, as confirmed by the modeling of the relaxation profiles. Our study advances understanding of ion dynamics in azole-based eutectic solvents, supporting their potential use in safer battery electrolytes. Full article

Unsymmetrical dimethylhydrazine (UDMH), a highly toxic rocket propellant, remains a significant environmental concern in Kazakhstan due to repeated rocket stage falls near the Baikonur Cosmodrome. This study integrates chemical analysis with stochastic contamination transport modeling to evaluate the persistence and migration of UDMH transformation products (TPs) in soils collected 15 years after the rocket crash. Vacuum-assisted headspace solid-phase microextraction coupled with gas chromatography–mass spectrometry (Vac-HS-SPME-GC-MS) was used to determine five major TPs. Among these, pyrazine (PAN) and 1-methyl-1H-pyrazole (MPA) were consistently detected at concentrations ranging from 0.04–2.35 ng g⁻¹ and 0.06–3.48 ng g⁻¹, respectively. Stochastic simulations performed with HYDRUS-1D indicated that the long-term persistence of these compounds is mainly controlled by physical nonequilibrium transport processes, including diffusion-limited exchange, weak sorption, and slow inter-domain mass transfer, rather than by degradation. Sensitivity analysis demonstrated that low dispersivity and diffusion coefficients enhance solute retention within immobile domains, maintaining residual levels over extended periods. The results demonstrate the efficacy of combined long-term monitoring and predictive modeling frameworks for assessing contamination dynamics in rocket impact zones. Full article

Imidazothiazoles are important and attractive scaffolds for the design of potential biologically active small molecules. Dialkylenamines are convenient building blocks and are often used as intermediate reagents for the synthesis of various heterocyclic systems such as pyrimidine, pyridine, pyrazole, etc. In the present paper, the simple and effective synthesis of (Z)-6-((dimethylamino)methylene)-2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one (2) is reported. The proposed method, based on the reflux of 2-methyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one with N,N-dimethylformamide dimethyl acetal, leads to an 80% yield of title compound 2. The structure of the synthesized compound 2 was confirmed using ¹H, ¹³C NMR, and LC-MS spectra. The applied protocol demonstrates practical advantages such as the absence of a solvent, a simple work-up, and the possibility of scale-up. Full article

The reaction of imidazole-5-carbohydrazide 1 with hydrazonyl halides 2a,b gave the corresponding hydrazide–hydrazone derivatives 3a,b. Afterwards, 3-methyl-5-(4-methyl-2-aryl-1H-imidazol-5-yl)-4-(2-phenylhydrazineylidene)-4H-pyrazole 4a,b was affordably produced by cyclizing the latter compounds 3a,b in EtOH with Et₃N at reflux temperature. The corresponding piperidinyl, morpholinyl, and piperazinyl derivatives 5a–f were produced by a nucleophilic substitution reaction of 3a,b with piperidine, morpholine, and 1-methylpiperazine in EtOH at reflux temperature. The condensation reaction of carbohydrazide 1 with either 3-acetyl-2H-chromen-2-one or 1-(benzofuran-2-yl)ethan-1-one in EtOH with AcOH at reflux temperature yielded the corresponding hydrazones 6 and 7, respectively, in excellent yields. Twelve compounds were evaluated for their antibacterial properties and to ascertain their minimum inhibitory concentrations utilizing well diffusion methods. All compounds showed differing levels of antibacterial efficacy depending on the microbial species. Compounds 4b and 5c had the most favorable results, with inhibition zones of 2.7 cm against the Gram-positive bacterium S. aureus, with a minimum inhibitory concentration (MIC) of 50 µg/mL. Compounds 4b and 5c, demonstrating the highest activity, were subjected to molecular docking investigations to evaluate their inhibitory effects on the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase [GlcN-6-P] of 2VF5. The molecular docking results revealed that both 4b and 5c exhibited a minimum binding energy of −8.7 kcal/mol, whereas the natural ligand GLP displayed a binding energy of −6.2 kcal/mol, indicating a substantial affinity for the active site; thus, they may be considered potent inhibitors of GlcN-6-P synthase. Full article

Coplanar tridentate nitrogen-donor ligands have been extensively employed to stabilize transition metal complexes by chelation. Some complexes exhibit interesting structures and photoluminescent properties. In this work, 2,6-bis(5-isopropyl-1H-pyrazole-3-yl)pyridine (denoted as L), its iron(II) and manganese(II) dichlorido complexes, and its bis-chelate iron(II) complexes, viz. [FeCl₂(L)]·2(MeOH) and [MnCl₂(L)]·2(MeOH), and [Fe(L)₂](PF₆) ·5(thf), respectively, were synthesized and characterized by single-crystal X-ray structural analysis. These solid-state structures contained N–H donors that formed hydrogen bonds with the coordinated halogenide ions and lattice solvent molecules, methanol or tetrahydrofuran. The iron(II) and manganese(II) dichlorido complexes [FeCl₂(L)]·2(MeOH) and [MnCl₂(L)]·2(MeOH) displayed distorted trigonal pyramidal structures in the solid state. However, [FeCl₂(L)]·2(MeOH) was not stable in methanol and formed the bis-chelate iron(II) complex [Fe(L)₂](FeCl₄). Therefore, the bis-chelate iron(II) complex [Fe(L)₂](PF₆)·5(thf) was also synthesized and structurally and spectroscopically authenticated. Full article

Background: Chagas disease poses a significant public health challenge, particularly impacting socioeconomically vulnerable populations. Current treatment strategies still rely on two nitro heterocyclic compounds: benznidazole and nifurtimox. Both agents exhibit limited therapeutic efficacy during the chronic phase of the disease and are often linked to severe adverse effects that frequently lead to treatment discontinuation. This urgent need for safer, more effective oral treatments drives the development of novel chemotypes. Objective: In this study, we advanced the preclinical evaluation of 4-imidazoline-1H-pyrazole derivatives, which have been identified as promising candidates against Trypanosoma cruzi. Methods: The candidate compound identified from the reversibility assay underwent further evaluation for its efficacy using a three-dimensional (3D) culture model and a Transwell co-culture system, in addition to the in vivo assessment. Results: Our findings revealed that compound 3m (3-Cl, 4-CH₃) exhibited low cytotoxicity while substantially decreasing the parasite burden in 3Dcardiac spheroid models. The compound effectively permeated Caco-2 cell monolayers and demonstrated the ability to inhibit T. cruzi infection in Vero cell cultures within a co-culture system. Furthermore, the 3m derivative not only controlled parasite resurgence but also showed significant therapeutic benefits in a murine model of acute T. cruzi infection, resulting in marked reductions in parasitemia and tissue parasitism, associated with diminished inflammatory infiltrate and cardiac fibrosis. Treatment with 3m increased the survival rate of infected mice to 40%, comparable to the reference drug benznidazole in several key pathological endpoints. Conclusion: These findings highlight the potential of 4-imidazoline-1H-pyrazole derivatives, particularly compound 3m, in mitigating the pathological effects associated with T. cruzi infection. Full article

Cyclopropanes are important in drug discovery because their unique structure, including inherent three-dimensionality, can enhance a drug’s properties, such as metabolic stability, target binding, and membrane permeability. In this communication, (5R*,6R*) 11-benzoyl-4,10-dimethyl-2,8-diphenyl-2,3,8,9-tetraazadispiro[4.0.4⁶.1⁵]undeca-3,9-diene-1,7-dione was prepared via a stereoselective one-pot reaction of phenylglyoxal hydrate with two equivalents of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one in EtOH in the presence of sodium acetate and N-bromosuccinimide. The structure of the newly synthesized compound was established by ¹H and ¹³C NMR, IR spectroscopy, high-resolution mass spectrometry, and elemental analysis. Full article

A new synthetic strategy for pyrazolo[1,5-d][1,2,4]triazin-7(6H)-ones 4 through intramolecular cyclization of alkyl 2-(4-nitro-1H-pyrazol-3-yl)methylene)hydrazine-1-carboxylates 3 is described, allowing us to selectively modify the N-substituent in 3-position. The reduction in nitro compounds 4 with tin(II) chloride leads to amines 5, and their acetylation leads to acetamides 6. Via alkylation of 4 with bromoacetic acid alkyl esters and 2-chloro-5-(chloromethyl)pyridine, and the subsequent reduction in alkylated nitro compounds 7, the corresponding amines 8 and amides 9 were accessible in very good yields. The molecular structure of ethyl 2-(2-morpholino-3-nitro-7-oxopyrazolo[1,5-d][1,2,4]triazin-6(7H)-yl)acetate (7b) was confirmed by single-crystal X-Ray diffraction analysis. Antibacterial and cytotoxic properties were evaluated for 61 synthesized compounds. Full article

In recent years, we have observed a growing interest in molecular hybridization, which involves combining chemically and pharmacologically diverse fragments into a single molecule. In this study, we designed and synthesized a series of indole–pyrazole hybrids, variously substituted at the pyrazole ring. The compounds were characterized by spectroscopic methods, and the structures of most of them were confirmed by X-ray analysis. Reactions of 3-(dimethylaminomethyl)indole with bromo-methyl-pyrazole derivatives proceeded in a tautomer-selective mode: the 4-bromo-3(5)-methyl-((1H-pyrazol-1-yl)methyl)-1H-indole tautomers, obtained from the 4-bromo-3-methyl-1H-pyrazole, could be isolated by column chromatography. In contrast, the 3-bromo-5-methyl-1H-pyrazole yielded the ((5-bromo-3-methyl-1H-pyrazol-1-yl)methyl)-1H-indole as the dominant reaction product. The 3-bromo-5-methyl tautomer could not be isolated nor could its presence be identified in solution. However, traces of it were recognized in the crystal of 5-bromo-3-methyl tautomer as a binary solid solution. In silico studies provided the physicochemical parameters of all compounds, enabling the estimation of some derivatives affinity to certain enzymes. In vitro evaluation of the hemolytic and cytoprotective properties of all derivatives showed that most of the compounds exhibited no hemolytic activity, while all demonstrated significant cytoprotective effects on human erythrocytes under oxidative stress. Full article