Search Results (35)

The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor potential cation channel, subfamily C, member 6 (TRPC6) modulator, offering a promising pathway for Alzheimer’s disease (AD) therapy. Our recent findings identify cmp2 as a novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood–brain barrier (BBB) penetration. In vivo studies demonstrate that cmp2 (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits in 5xFAD mice. This study further shows cmp2’s selectivity towards tetrameric TRPC6 channel in silico. Acute administration of cmp2 is non-toxic, with no indications of chronic toxicity, and Ames testing confirms its lack of mutagenicity. Behavioral assays reveal that cmp2 improves cognitive functions in 5xFAD mice, including increased novel object recognition, better passing of the Morris water maze, and improved fear memory, as well as upregulation of motor function in beam walking tests. These findings suggest that cmp2 holds promise as a candidate for AD treatment. Full article

The hydroxylated perhydroquinoxaline 14 was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of 14 comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (4). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane 7 by the reaction of dialdehyde 6 with benzylamine and nitromethane. The piperazine ring was annulated by the reaction of silyloxy-substituted cyclohexanetriamine 8 with dimethyl oxalate. The pharmacophoric structural elements characteristic for κ receptor agonists were finally introduced by functional group modifications. The structure including the relative configuration of the tetrasubstituted cyclohexane derivative (2r,5s)-7a and the perhydroquinoxaline 9 was determined unequivocally by X-ray crystal structure analysis. The hydroxylated perhydroquinoxaline 14 showed moderate κ receptor affinity (K_i = 599 nM) and high selectivity over μ, δ, σ₁, and σ₂ receptors. An ionic interaction between the protonated pyrrolidine of 14 and D138 of κ receptor anchors 14 in the κ receptor binding pocket. Full article

A series of novel vindoline–piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI₅₀) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI₅₀ = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI₅₀ = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC₅₀) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds. Full article

Although Hantzsch synthesis has been an established multicomponent reaction method for more than a decade, its derivative, whereby an aniline replaces ammonium acetate as the nitrogen source, has not been explored at great length. Recent studies have shown that the products of such a reaction, N-aryl-4-aryldihydropyridines (DHPs), have significant anticancer activity. In this study, we successfully managed to synthesize a wide range of DHPs (18 examples, 8 of which were novel) using a metal-free, mild, inexpensive, recoverable, and biopolymer-based heterogeneous catalyst, known as piperazine, which was supported in agar–agar gel. In addition, 8 further examples (3 novel) of such dihydropyridines were synthesized using isatin instead of aldehyde as a reactant, producing spiro-linked structures. Lastly, this catalyst managed to afford an unprecedented product that was derived using an innovative technique—a combination of multicomponent reactions. Essentially, the product of our previously reported aza-Friedel–Crafts multicomponent reaction could itself be used as a reactant instead of aniline in the synthesis of more complex dihydropyridines. Full article

The degradation of fluoroquinolones (FQs) via advanced oxidation processes (AOPs) is a promising avenue, yet the complete mineralization of certain FQ molecules remains elusive, raising concerns about the formation of toxic by-products. This study delineates five primary AOP degradation pathways for 16 commercially available FQ molecules, inferred from existing literature. Density functional theory (DFT) was employed to calculate the bond dissociation energies within these pathways to elucidate the correlation between bond strength and molecular architecture. Subsequently, Comparative Molecular Similarity Index Analysis (CoMSIA) models were constructed for various degradation reactions, including piperazine ring cleavage, defluorination, hydroxylation, and piperazine ring hydroxylation. Three-dimensional contour maps generated from these models provide a deeper understanding of the interplay between FQ molecular structure and bond dissociation energy. Furthermore, toxicity predictions for 16 FQ molecules and their advanced oxidation intermediates, conducted using VEGA 1.2.3 software, indicate that degradation products from pathways P2 and P5 pose a heightened health risk relative to their parent compounds. Furthermore, the application of the Multwfn program to compute the Fukui function for FQ molecules discerns the disparity in degradation propensities, highlighting that N atoms with higher f0 values can augment the likelihood of piperazine ring cleavage. HOMO-LUMO distribution diagrams further confirm that methoxy substitution at the 1-position leads to a dilution of HOMOs on the piperazine ring and an increased energy gap for free radical reactions, diminishing the reactivity with hydroxyl radicals. This study elucidates the pivotal role of structural characteristics in FQ antibiotics for their degradation efficiency within AOPs and unveils the underlying mechanisms of bond dissociation energy disparities. The toxicity parameter predictions for FQ molecules and their intermediates offer unique perspectives and theoretical underpinnings for mitigating the use of high-risk FQs and for devising targeted degradation strategies to circumvent the generation of toxic intermediates in AOPs through molecular structure optimization. Full article

The unrestricted utilization of antibiotics poses a critical challenge to global public health and safety. Levofloxacin (LEV) and sulfaphenazole (SPN), widely employed broad-spectrum antimicrobials, are frequently detected at the terminal stage of water treatment, raising concerns regarding their potential conversion into detrimental disinfection byproducts (DBPs). However, current knowledge is deficient in identifying the potential DBPs and elucidating the precise transformation pathways and influencing factors during the chloramine disinfection process of these two antibiotics. This study conducts a comprehensive analysis of reaction pathways, encompassing piperazine ring opening/oxidation, Cl-substitution, OH-substitution, desulfurization, and S−N bond cleavage, during chloramine disinfection. Twelve new DBPs were identified in this study, exhibiting stability and persistence even after 24 h of disinfection. Additionally, an examination of DBP generation under varying disinfectant concentrations and pH values revealed peak levels at a molar ratio of 25 for LEV and SPN to chloramine, with LEV contributing 11.5% and SPN 23.8% to the relative abundance of DBPs. Remarkably, this research underscores a substantial increase in DBP formation within the molar ratio range of 1:1 to 1:10 compared to 1:10 to 1:25. Furthermore, a pronounced elevation in DBP generation was observed in the pH range of 7 to 8. These findings present critical insights into the impact of the disinfection process on these antibiotics, emphasizing the innovation and significance of this research in assessing associated health risks. Full article

In the present paper, the photophysical properties of metallocene-4-amino-1,8-naphthalimide-piperazine molecules (1-M²⁺), as well as their oxidized and protonated derivatives (1−M³⁺, 1-M²⁺-H⁺, and 1-M³⁺-H⁺), where M = Fe, Co, and Ni, were studied via DFT and TD-DFT, employing three functionals, i.e., PBE0, TPSSh, and wB97XD. The effect of the substitution of the transition metal M on their oxidation state, and/or the protonation of the molecules, was investigated. The present calculated systems have not been investigated before and, except for the data regarding their photophysical properties, the present study provides important information regarding the effect of geometry and of DFT methodology on absorption spectra. It was found that small differences in geometry, specifically in the geometry of N atoms, reflect significant differences in absorption spectra. The common differences in spectra due to the use of different functionals can be significantly increased when the functionals predict minima even with small geometry differences. For most of the calculated molecules, the main absorption peaks in visible and near-UV areas correspond mainly to charge transfer excitations. The Fe complexes present larger oxidation energies at 5.4 eV, whereas Co and Ni complexes have smaller ones, at about 3.5 eV. There are many intense UV absorption peaks with excitation energies similar to their oxidation energies, showing that the emission from these excited states can be antagonistic to their oxidation. Regarding the use of functionals, the inclusion of dispersion corrections does not affect the geometry, and consequently the absorption spectra, of the present calculated molecular systems. For certain applications, where there is a need for a redox molecular system including metallocene, the oxidation energies could be lowered significantly, to about 40%, with the replacement of the iron with cobalt or nickel. Finally, the present molecular system, using cobalt as the transition metal, has the potential to be used as a sensor. Full article

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC₅₀ value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC. Full article

The existence of heteroatomic compounds with complex structure and different polarity in the asphaltene of medium and low temperature coal tar (M/LTCT) limits its processing and utilization. Combined with negative ion electrospray ionization source (ESI), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was used to characterize the molecular composition of O, N, and S heteroatom compounds in M/LTCT asphaltenes. Acidic oxygen-containing compounds (OCCs) and non-basic nitrogen-containing compounds (NCCs) in asphaltenes were identified, except for sulfur-containing compounds (SCCs). The mass spectra showed that the heteroatom compounds in asphaltene mainly existed as N_X, N₁O_X, N₂O_X, N₃O_X, N₄O_X, N₅O_X, N₆O_X, and O_X class species (where x = 1–6). The M/LTCT asphaltenes were enriched with O₄, N₄, and N₁O₁ class species. The core structure of O₄ class species were likely to be composed of 1–7 aromatic rings with 4 phenolic hydroxyl groups, the core structure of N₄ class species were likely to be comprised of 4–7 aromatic rings with a piperazine ring and a pyrazole ring, and the core structure of N₁O₁ was mainly 3–6 aromatic rings with a phenolic hydroxyl group and a pyrrole ring. These results suggest that more condensed NCCs and OCCs with short, substituted alky side chains are presented, which are more easily to undergo condensation to generate fused molecules, making it too difficult to be removed by hydrogenation. Through the analysis of the molecular structures of OCCs and non-basic NCCs in M/LTCT asphaltenes, important information about the molecular composition can be obtained, which can provide basic data for the hydrogenation of deasphaltene. Full article

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenucleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpiperazines represents one of the most important classes of 5-HT_1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharmacophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT_1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study. Full article

Cancer is one of the greatest challenges in modern medicine today. Difficult and long-term treatment, the many side effects of the drugs used and the growing resistance to treatment of neoplastic cells necessitate new approaches to therapy. A very promising targeted therapy is based on direct impact only on cancer cells. As a continuation of our research on new biologically active molecules, we report herein the design, synthesis and anticancer evaluation of a new series of N-Mannich-base-type hybrid compounds containing morfoline or different substituted piperazines moieties, a 1,3,4-oxadiazole ring and a 4,6-dimethylpyridine core. All compounds were tested for their potential cytotoxicity against five human cancer cell lines, A375, C32, SNB-19, MCF-7/WT and MCF-7/DX. Two of the active N-Mannich bases (compounds 5 and 6) were further evaluated for growth inhibition effects in melanoma (A375 and C32), and normal (HaCaT) cell lines using clonogenic assay and a population doubling time test. The apoptosis was determined with the neutral version of comet assay. The confocal microscopy method enabled the visualization of F-actin reorganization. The obtained results demonstrated that compounds 5 and 6 have cytotoxic and proapoptotic effects on melanoma cells and are capable of inducing F-actin depolarization in a dose-dependent manner. Moreover, computational chemistry approaches, molecular docking and electrostatic potential were employed to study non-covalent interactions of the investigated compounds with four receptors. It was found that all the examined molecules exhibit a similar binding affinity with respect to the chosen reference drugs. Full article

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC₅₀ = 70 nM for Bcr-Abl), 5j (IC₅₀ = 0.41 μM for BTK) and 5b (IC₅₀ = 0.38 μM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs. Full article

Neuroinflammation involves activation of glial cells in the brain, and activated microglia play a particularly important role in neurodegenerative diseases such as Alzheimer’s disease (AD). In this study, we developed 5-cyano-N-(4-(4-(2-[¹⁸F]fluoroethyl)piperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([¹⁸F]1) for PET imaging of colony-stimulating factor 1 receptor (CSF1R), an emerging target for neuroinflammation imaging. Non-radioactive ligand 1 exhibited binding affinity comparable to that of a known CSF1R inhibitor, 5-cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide (CPPC). Therefore, we synthesized radioligand [¹⁸F]1 by radiofluorination of chlorine-substituted precursor 7 in 13–15% decay-corrected radiochemical yield. Dynamic PET/CT images showed higher uptake in the lipopolysaccharide (LPS)-treated mouse brain than in control mouse brain. Ex vivo biodistribution study conducted at 45 min after radioligand injection showed that the brain uptake in LPS mice increased by 78% compared to that of control mice and was inhibited by 22% in LPS mice pretreated with CPPC, indicating specificity of [¹⁸F]1 for CSF1R. A metabolism study demonstrated that the radioligand underwent little metabolism in the mouse brain. Taken together, these results suggest that [¹⁸F]1 may hold promise as a radioligand for CSF1R imaging. Full article

This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6a–g, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/z_measured via HPLC-UV/HR-MS, log ε_{2 (Ch–T)} from UV/Vis spectrophotometry and log k_w via RP-HPLC) as well as in vitro antimycobacterial and cytotoxic screening of given compounds were carried out (i.e., determination of MIC and IC₅₀ values). These highly lipophilic molecules (log k_w = 4.1170–5.2184) were tested against Mycobacterium tuberculosis H₃₇R_a ATCC 25177 (Mtb H₃₇R_a), M. kansasii DSM 44162 (MK), M. smegmatis ATCC 700084 (MS), and M. marinum CAMP 5644 (MM). The impact of the 6a–g set on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated. 1-[2-Hydroxypropyl-{(3-trifluoromethyl)- phenyl}carbamoyloxy]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride (6e) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (6g) most effectively inhibited the growth of Mtb H₃₇R_a (MIC < 3.80 μM). The substance 6g also showed interesting activity against MM (MIC = 8.09 μM). All obtained data served as input values for structure-activity relationship evaluations using statistical principal component analysis. In fact, the toxicity of both 6e (IC₅₀ = 29.39 μM) and 6g (IC₅₀ = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe. Full article

The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling. Full article