Search Results (144)

Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. Full article

EGFR is the most frequently altered driver gene in non-small-cell lung cancer (NSCLC), and its overexpression is also associated with breast cancer. In the present study, we synthesized 18 new compounds (B-1, B-2, B-6, B-7, and BP-1–14). The cytotoxicity of these compounds was evaluated in A549 NSCLC and MCF-7 breast cancer cells, as well as in Jurkat cells and PBMCs (healthy). The most potent compounds were further examined for their ability to induce apoptosis in A549 and MCF-7 cells, as well as their EGFR inhibitory activity. Molecular docking was conducted at the ATP-binding site of EGFR, and key pharmacokinetic and toxicity parameters were predicted in silico. B-2 demonstrated the strongest cytotoxicity against A549 and MCF-7 cells (IC₅₀ = 2.14 ± 0.83 μM and 8.91 ± 1.38 μM, respectively), displaying selective cytotoxicity between Jurkat cells and PBMCs (SI = 23.2). B-2 induced apoptosis in A549 and MCF-7 cells at rates of 16.8% and 4.3%, respectively. B-2 inhibited EGFR by 66% at a 10 μM concentration and showed a strong binding affinity to the ATP-binding site of EGFR. Furthermore, B-2 exhibited drug-like characteristics and was not identified as carcinogenic, genotoxic, or mutagenic. B-2 shows promise as an apoptosis inducer and EGFR inhibitor for future anti-NSCLC and anti-breast cancer research. Full article

Nitrogen-containing heterocycles are fundamental scaffolds in organic chemistry, particularly due to their prevalence in pharmaceuticals, agrochemicals and materials science. Among them, five-membered rings, containing two nitrogen atoms in adjacent positions—such as pyrazoles, pyrazolines and indazoles—are especially significant due to their versatile biological activities and structural properties, which led to the search for greener, faster and more efficient methods for their synthesis. Conventional batch synthesis methods, while effective, often face challenges related to reaction efficiency, scalability and safety. Flow chemistry has emerged as a powerful alternative, offering enhanced control over reaction parameters, improved safety profiles and opportunities for scaling up synthesis processes efficiently. This review explores the impact of flow chemistry on the synthesis of these pivotal heterocycles, highlighting its advantages over the conventional batch methods. Although indazoles have a five-membered ring fused with a benzene ring, they will also be considered in this review due to their biological relevance. Full article

The world today is being ravaged by the emergence and re-emergence of microbial infections caused by antimicrobial-resistant strains, brought about primarily by the frequent and perhaps unnecessary use of antimicrobial agents. A need therefore arises to develop new antimicrobial drugs that can combat these pathogens resistant to currently available antibiotics. This present study has adopted a multi-enzyme in silico approach in evaluating new 2-pyrazolines as antimicrobial agents, targeting and aiming to inhibit three pivotal enzymes in the bacteria’s life cycle. A library of 2-pyrazolines was tailored to achieve the desired activity. The library of compounds and amoxicillin, a standard antimicrobial drug, were docked into the molecular target enzymes. They were also subjected to toxicity and drug-likeness tests, using PROTOX and swissADME, respectively. A moderate toxicity profile was indicated, as more than 90% of the ligands were in ProTox class 4. The majority exhibited advantageous ADME characteristics. A significant number of them demonstrated a binding affinity for the target proteins that was stronger than both the native ligand and the binding affinity of amoxicillin. Ligands 30, 20, and 8 are the notable ones across all target enzymes. These results suggest that these novel ligands may be powerful inhibitors, particularly when it comes to interfering with the formation of bacterial cell walls, folic acid, and nucleotide metabolism. Additional in vivo and in vitro research is required to confirm these results and evaluate their therapeutic potential. Full article

Background: Despite recent breakthroughs in cancer treatment, non-small cell lung cancer (NSCLC) and breast cancer remain major causes of death from all malignancies. The epidermal growth factor receptor (EGFR) is an important mediator of the pathways involved in cell proliferation, apoptosis, and angiogenesis. Thus, its overexpression triggers several types of cancer, including NSCLC and breast cancer. Methods: In the current study, we synthesized new pyrimidine-tethered compounds (chalcone derivative (B-4), pyrazoline–carbothioamide (B-9), and pyrazoline–thiazole hybrids (BH1-7)). These compounds were then tested for cytotoxicity against A549 NSCLC and MCF-7 breast cancer cells. Results: Of these, B-4 displayed significant cytotoxicity against both cells (IC₅₀ = 6.70 ± 1.02 µM for MCF-7; IC₅₀ = 20.49 ± 2.7 µM for A549) compared to the standard agent lapatinib (IC₅₀ = 9.71 ± 1.12 µM for MCF-7; IC₅₀ = 18.21 ± 3.25 µM for A549). The anticancer potential of B-4 between Jurkat leukemic T cells and peripheral blood mononuclear cells (PBMCs) (healthy) was found to be selective. Mechanistically, 11.9% and 10.2% of A549 and MCF-7 cells treated with B-4, respectively, underwent apoptosis and B-4 produced 46% EGFR inhibition at a concentration of 10 μM. The B-4/EGFR complex obtained after induced fit docking was subjected to 300 ns of molecular dynamics simulation, which confirmed the stability of the complex in a mimicked biological environment. On the other hand, B-4 was shown to have drug-like properties by in silico pharmacokinetic estimation. Conclusions: B-4 is an EGFR inhibitor and apoptosis inducer for future NSCLC and breast cancer studies. Full article

The synergistic solvent extraction of La(III), Eu(III) and Lu(III) with a chelating extractant, 4-benzoyl-3-methyl-1-phenyl-2-pyrazolin-5-one (HL), and neutral bidentate heterocyclic amines, such as 1,10-phenanthroline (S1 (phen)) or 2,2′-bipyridine (S2 (bipy)) in an ionic liquid of the imidazolium family [C₁C₄im⁺][Tf₂N⁻] was investigated. Synergistic effects have been observed to result from the formation of a ternary complex in the organic phase, particularly in cases where the ligand S is a neutral synergistic agent. Examples include La(L)₂(S2)₂, Eu(L)₃(S2) and Lu(L)_x(S2)₂, as well as La(L)₃(S1)₂, Eu(L)₂(S1) and Lu(L)₃(S1)_x). The parameters of the solvent extraction process were determined and the influence of the synergistic agent on the extraction process was discussed. Additionally, the synergistic increase and separation factors were determined. The equilibrated organic phases were analyzed using ¹H NMR spectroscopy to elucidate the synergism in an extraction mechanism. The role of the ionic diluent in complexation processes and selectivity was investigated with the employment of the two synergistic agents for various metal s-, p-, d- and f-cations in the periodic table, with almost 22 metal ions. Full article

In this paper, we report a highly regioselective 1,3-dipolar cycloaddition (1,3-DC) reaction of nitrilimines with thioaurone derivatives that afforded the hitherto unreported spiropyrazolines. Spectroscopic and spectrometric data were utilized to confirm the structure of all products and elucidate the reaction’s regiochemistry. A mechanistic study was performed within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311G(d,p) computational level to explain the regioselectivity observed. The electron localization function (ELF) topological analysis confirms the carbenoid-type (cb-type) mechanism of the cycloaddition reactions between nitrilimines and thioaurones. The intermolecular interactions between reagents in this reaction account for the regioselectivity observed experimentally. Full article

Malaria, a devastating disease caused by Plasmodium parasites, continues to pose a significant threat to global health, with increasing resistance to current antimalarial drugs. In this study, we employed an in silico approach to design and evaluate novel 2-pyrazoline carboxamide derivatives as potential protease inhibitors against Plasmodium falciparum. Our results show that all the designed ligands exhibit good drug-like properties, satisfying Lipinski’s rule of five, and have low toxicity profiles. Molecular docking studies revealed that five newly designed ligands (P5, P6, P7, P11, and P13) exhibit promising binding affinities and interactions with key protease enzymes involved in the hemoglobin degradation pathway, including Falcipain-2, Falcipain-3, and Plasmepsin-2 with PDB (Protein Data Bank) codes of 6JW9, 3BWK, and 1LF3, respectively. Notably, ligand P13 showed the strongest binding affinity with Falcipain-2, forming an additional hydrogen bond with CYS42, an essential residue for the enzyme’s catalytic activity. The interactions between the ligands and the enzymes suggest a competitive inhibition mechanism, with the potential to disrupt the hemoglobin degradation pathway and halt the parasite’s lifecycle. The biological implications of these findings are significant, as they suggest that these novel ligands could be effective against Plasmodium parasites, particularly in the context of increasing resistance to current antimalarial drugs. Overall, this study provides valuable insights into the potential of novel 2-pyrazoline carboxamide derivatives to serve as protease inhibitors against Plasmodium parasites, highlights their potential as a promising strategy for antimalarial drug development, and demonstrates the importance of in silico approaches in the discovery of novel therapeutics. Full article

The cycloaddition of nitrile oxides and nitrilimines to one or both of the C=C double bonds of caryophyllene is described. The possibility of introducing five-membered fused and spiro-linked heterocycles into the structure of sesquiterpenes by the 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrilimines to caryophyllene was demonstrated. As a result of these reactions, pharmacophore fragments of isoxazoline and pyrazoline are introduced into the structure of caryophyllene, which leads to an increase in the conformational rigidity of the molecule. A complete stereochemical assignment of 1,3-dipolar cycloaddition adducts to caryophyllene was carried out. The study of antiviral and cytotoxic activity for some heterocyclic derivatives synthesized in this work revealed relatively high biological activity of previously little-studied cycloaddition adducts at the exocyclic C=CH₂ bond of caryophyllene. The effect of substituents in the synthesized heterocycles on biological activity was demonstrated. Compounds with a good inhibitory effect on the H1N1 influenza virus were revealed. The activity of the compound was demonstrated up to 6 h post infection, and this could be due to slight inhibiting activity against viral neuraminidase, necessary at the stage of progeny virion budding. Full article

Presently, a major challenge is the search for new compounds that may exhibit an inhibitory effect on tumor progression. Recently, the 4-thiazolidinone (4-TZD) group has gained attention in this research field. The aim of the present study was to evaluate the anticancer effects of two new 4-TZD-based derivatives (Z)-5-[5-(2-hydroxyphenyl)- (Les- 4368) and (Z)-5-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-ones (Les-4370) on peroxisome proliferator-activated receptor gamma (PPARγ)-dependent cytotoxicity in human colorectal adenocarcinoma cells (CACO-2) and in normal human fibroblasts (BJ) in vitro. Les-4368 and Les-4370 exerted a toxic effect on both tested cell lines in high (micromolar) concentrations (10–100 µM). In addition, Les-4368 and Les-4370 applied in the BJ and CACO-2 cells in the concentration range of 10 µM to 100 µM increased the activity of caspase-3 and the production of reactive oxygen species (ROSs). The mRNA expression of PPARγ-related genes (PPARγ, AhR, PXR, and NF-κB) showed certain changes in these parameters, proving the engagement of this receptor in the induction of the biological effects of both tested 4-TZD derivatives. Moreover, the treatment of the BJ and CACO-2 cells with Les-4368, Les-4370, an antagonist (GW9662), or an agonist (rosiglitazone) of the PPARγ receptor also resulted in changes in the above-mentioned parameters. Unfortunately, the tested substances studied cell line work in a non-selective way at a relatively high concentration, which reduces their potential for clinical application. Our research is the preliminary study with the use of these compounds and requires further studies to elucidate the mechanisms of action of their anticancer potential. Full article

This study evaluates the antiproliferative potential of flavanones, chromanones and their spiro-1-pyrazoline derivatives as well as their inclusion complexes. The main goal was to determine the biological basis of molecular pro-apoptotic activities and the participation of reactive oxygen species (ROS) in shaping the cytotoxic properties of the tested conjugates. For this purpose, changes in mitochondrial potential and the necrotic/apoptotic cell fraction were analyzed. Testing with specific fluorescent probes found that ROS generation had a significant contribution to the biological anticancer activity of complexes of flavanone analogues. TT (thrombin time), PT (prothrombin time) and APTT (activated partial tromboplastin time) were used to evaluate the influence of the compounds on the extrinsic and intrinsic coagulation pathway. Hemolysis assays and microscopy studies were conducted to determine the effect of the compounds on RBCs. Full article

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone β-carbon with the furanyl moiety and structural modification of the α,β-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC₅₀ values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII–X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔG_bin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays. Full article

Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells. Full article

Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure. Full article

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer’s disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications. Full article