Search Results (35)

Aminosteroid derivative RM-581 stands out as an anticancer agent, supported by positive in vitro and in vivo studies on resistant cancers of the breast, prostate, and pancreas. A synthetic route has already been developed to obtain aminosteroid RM-581 in small quantities (scale of milligrams to a few grams). However, this route has significant limitations in view of its transposition to scaling up to larger quantities to support late preclinical and clinical trials. Among the problems are the use of toxic reagents, the moderate overall yield, and the need for multiple purifications through chromatographic columns. The development of a new synthetic route has therefore been explored. Starting from commercially available estrone, 2,4-dibromo-estrone was rapidly formed, followed by the regioselective introduction of a nitro group at the C2 position and by the methylation of phenol at the C3 position. The 4-bromo-2-nitro-3-O-methylestrone was then reduced to 2-amino-3-O-methylestrone and the primary amine was used to form the piperazine ring. Once the cyclization step was carried out, the last two steps were identical to the first synthetic route previously reported, i.e., introducing an ethynyl group at the C-17α position and then adding the quinoline-proline side chain with an N-acylation, assisted by a peptide coupling reagent. Importantly, no purification by chromatography was necessary during the whole sequence of reactions and only a final silica gel filtration, followed by recrystallization, led to RM-581 at a very high level of purity. The structure was also fully characterized by 2D NMR analysis. Full article

The present study reports the application of three copper(II) coordination polymers, namely ¹_∞[Cu₃L₂(N₃)] CH₃COO (CP1), ¹_∞[Cu₃L₂(NO₃)]NO₃·2CH₃OH·2H₂O (CP2), and ¹_∞[Cu₃L₂(H₂O)](ClO₄)₂ (CP3), where H₂L stands for N,N′-bis[(2-hydroxybenzilideneamino)propyl]-piperazine) as catalysts for photocatalytic degradation of Acid Orange 7 and Methyl Orange dyes from single and binary aqueous solutions. The influence of the photocatalyst nature, hydrogen peroxide presence, reaction time, dye concentration, and catalyst dose on the photodegradation efficiency was studied. Under visible light irradiation, complex CP1 demonstrated the highest photodegradation efficiency of 92.40% and 80.50% towards Acid Orange 7 and Methyl Orange, respectively. The kinetic studies indicated that the photodegradation process followed a pseudo-first-order kinetics. The highest rate of the degradation process was obtained when CP1 is used, and the necessary time for the degradation of the dyes increases with increasing concentration of the dye solutions. The degradation efficiency of more than 75% after five recycling/reuse cycles of CP1 and the yields higher than 72% obtained for the degradation of dyes from the binary system demonstrate the photocatalytic capacity of CP1. A photocatalytic oxidation mechanism was proposed and the stability of the CP1 complex before and after the photodegradation process of dyes, both from simple and binary solutions, was investigated and confirmed. Full article

A series of 2- and 3-methoxyphenylpiperazine derivatives in combination with a 2-hydroxypropoxy linker and coumarins containing various substituents was synthesized and evaluated for antidepressant-like activity. Microwave-assisted synthesis was used, and the structures of all compounds were confirmed by ¹H, ¹³C NMR, and HRMS spectrometry. The affinity toward the 5-HT_1A and 5-HT_2A receptors was determined using radioligand binding assays and analyzed by molecular docking studies. Among the compounds evaluated, four demonstrated high affinity for the 5-HT_1A receptor with the following Ki values: 5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (5) (90 nM), 6-acetyl-5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (7) (90 nM), 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl) propoxy)-4-methyl-2H-chromen-2-one (10) (87 nM), and 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxy phenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (11) (96 nM), and four demonstrated high affinity for the 5-HT_2A receptor with the following Ki values: 6-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (2) (83 nM), 8-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (12) (67 nM), 7-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl) propoxy)-2H-chromen-2-one (13) (18 nM), and 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (14) (68 nM). In functional assays, 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxyphenyl) piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (compound 11) exhibited a significant 5-HT_1A antagonistic profile. Computational studies revealed the structural details responsible for the high affinity of selected derivatives, which were compared to known 5HT_1A partial agonists. Full article

In this study, three dinuclear copper(II) complexes of ligand 2,6-bis[(N-methyl-piperazine-1-yl)methyl]-4-formyl phenol (L1) and one of 2,6-bis[(N-methylpiperazine-1-yl)methyl]-4-formyl phenol dimethylacetal (L2) with copper(II) ions have been investigated as new types of biomimetic catalysts for the oxidative transformation of different aminophenols and phenyldiamines. All the complexes of interest were newly synthesized and further characterized by IR spectroscopy, UV-Vis and mass spectrometry, X-ray diffraction, and selected electrochemical measurements. Crystal structures of these dinuclear copper(II) complexes have revealed that the coordination-shell geometry of copper atoms is close to a tetragonal pyramid. Catecholase, phenoxazinone synthase, and horseradish peroxidase-like activities were observed in pure methanol and water–methanol mixtures in the presence of molecular oxygen. The potential applicability of the complexes under study is discussed with respect to their possibilities and limitations in the replacement of natural copper-containing oxidoreductases in the oxidative degradation of water-insoluble chlorinated aminophenols in the dye industry or in the production of phenoxazine-based drugs. 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

1-amino-4-methyl-piperazine (AMP) is both a starting material for the synthesis of rifampicin (RIF) and a degradation product of RIF hydrolysis. 1-methyl-4-nitroso-piperazine (MNP) is an oxidation product of AMP as well as a potentially genotoxic N-nitrosamine. The EMA and FDA have approved an ad interim limit of 5 ppm for MNP in RIF drug products. As in-house methods for the analysis of MNP in RIF use a wide range of conditions for mobile phases and sample diluents, we decided to investigate whether these conditions affect the formation of MNP and AMP. A UHPLC-MS/MS method was developed to simultaneously quantify AMP and MNP during RIF hydrolysis in buffered aqueous solutions at different pH levels. Analyses were performed in MRM mode; separations were carried out on an InfinityLab Poroshell HPH-C18 (100 mm, 2.1 mm i.d., particle size 1.9 μm). In aqueous RIF solutions, the content of AMP and MNP increases with time; at different pHs, the concentration of AMP increases much faster in acidic than in basic solutions; and the increase in MNP can be reduced by the addition of ascorbic acid. To avoid an overestimation of MNP, water should not be used as a diluent in RIF sample preparations. Methanol is a more suitable diluent than water. A standard addition method has been validated for the quantification of MNP in RIF drug substances. Full article

The wide range of biological processes and functions that benzimidazole moieties can be used for makes them very interesting synthetic molecules. A novel class of scaffolds for benzimidazole heterocycles has been successfully constructed in the present study and synthesized by using the starting material of O-phenylenediamine derivatives (1a–c). The 1-methyl-2-(methylthio)-1H-benzo[d]imidazole derivatives (3a–c) have been synthesized as intermediate compounds by treating the precursors (1a–c) with carbon disulfide followed by N- and S-methylation with iodomethane and anhydrous potassium carbonate. In the latter step, the intermediate molecules were converted into benzimidazole-containing methyl-piperazine (4a–c), piperazin-ol tethered benzimidazoles (5a–c), and phenylpiperazine holding benzimidazoles (6a–c). The structures assigned to target compounds have been analyzed and confirmed via IR, NMR, and MS analysis. The antibacterial, anthelmintic, and anticancer properties of the target compounds were examined. The biological study showed that the compounds 6b, 4c, and 5a emerge as excellent antibacterial, antifungal, and anthelmintic agents, respectively, whereas heterocycle 6a showed excellent anticancer activity against hepatocyte-derived cell line HUH7, as well as the MCF7 breast cancer cell line with IC₅₀ values of 6.41 and 9.70 µg/mL, respectively. The discovery of a novel class of hetero compounds with multiple hetero moieties that may aid in medication design is also highlighted in this study. Full article

Dubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical trials to determine its antineoplastic potential (CLL). In the current work, the Xenosite web predictor tool was employed to predict the vulnerable sites of metabolism and the reactivity pathways (cyanide and GSH) of DMB. Subsequently, we present the analysis and identification of in vitro and reactive intermediates of DMB using liquid chromatography ion trap mass spectrometry (LC–ITMS). Human liver microsomes (HLMs) were exposed to dimethylbenzene in a laboratory setting, and the resulting metabolites were collected through protein precipitation. Intense reactivity toward nucleophilic macromolecules was seen in the metabolites of the piperazine and pyrimidine rings in DMB, iminium, and 2,5-quinone-imine, respectively. To assess the toxicities of the possibly reactive metabolites, DMB was incubated with HLMs in the presence of 1.0 mM KCN and 1.0 mM glutathione. The DMB metabolites found by LC–MS/MS were seven in vitro phase I metabolites, three cyano adducts, and two GSH conjugates. Phase I in vitro metabolic reactions included N-demethylation, hydroxylation, and dechlorination. DMB and its metabolites have not been investigated for their metabolism in vitro. Full article

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC₅₀ of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC₅₀ = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with K_i values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC₅₀ of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC₅₀ of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases. Full article

In this study, by adding zirconium anhydride (ZrO₂) particles to a solution of N–methylmorphorphine–N–oxide (NMMO) and bamboo cellulose (BC), we used interfacial polymerization (IP) to obtain regenerated cellulose nanofiltration membranes (IP–ZrO₂/BC–NFMs) that exhibited high water flow and rejection of salts and dyes. During interfacial polymerization, anhydrous piperazine (PIP) was used as the waterborne monomer, and 1,3,5–trimesoyl chloride (TMC) and n–hexane were used as the organic phase. The procedure was adjusted by analyzing the impacts of the concentrations of the water and organic phase monomers and the reaction duration on the performance of the developed IP–ZrO₂/BC–NFMs. The chemical structures and morphologies of the as–obtained IP–ZrO₂/BC–NFMs were examined using various characterization techniques. The performance of these membranes for removal of inorganic salts and dyes as well as their water flow were investigated. IP–ZrO₂/BC–NFMs obtained at a pressure of 0.5 MPa, PIP concentration of 1.5 wt.%, TMC concentration of 0.15 wt.%, and polymerization period of 2 min displayed the highest water flux (55.12 LMH) and the best desalination effect (NaCl rejection rate = 19.15%). Over 90% of both Methyl Blue (MB) and Congo Red (CR) dyes were intercepted. We demonstrated that the addition of ZrO₂ to nanofiltration membranes significantly enhanced the water flow of the IP–ZrO₂/BC–NFMs as well as the salt ion rejection rate. 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

The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC₅₀ values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development. Full article

In this paper, a simple and clean process for the alkylation and arylation of nitrogen-containing heterocycles is reported. The reactions were conducted using the Q-tube® as a non-conventional technology, in water as a green solvent, at overboiling temperature. The developed strategy was used to improve two steps in the total synthesis of caffeine, as reported by Narayan, and then extended to the preparation of N-decorated xanthines. Finally, piperidine, methyl piperazine, and isatine were proven to be suitable substrates for the protocol proposed herein. Full article

In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the pK_a determination by ¹H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series of mono-substituted cationic single isomer CDs. The first series of selectors were mono-(6-N-pyrrolidine-6-deoxy)-β-CD (PYR-β-CD), mono-(6-N-piperidine-6-deoxy)-β-CD (PIP-β-CD), mono-(6-N-morpholine-6-deoxy)-β-CD (MO-β-CD) and mono-(6-N-piperazine-6-deoxy)-β-CD (PIPA-β-CD), carrying a pH-adjustable moiety at the narrower rim of the cavity, while the second set represented by their quaternarized, permanently cationic counterparts: mono-(6-N-(N-methyl-pyrrolidine)-6-deoxy)-β-CD (MePYR-β-CD), mono-(6-N-(N-methyl-piperidine)-6-deoxy)-β-CD (MePIP-β-CD), mono-(6-N-(N-methyl-morpholine)-6-deoxy)-β-CD (MeMO-β-CD) and mono-(6-N-(4,4-N,N-dimethyl-piperazine)-β-CD (diMePIPA-β-CD). Based on pH-dependent and selector concentration-dependent comparative studies of these single isomer N-heterocyclic CDs presented herein, it can be concluded that all CDs could successfully be applied as chiral selectors for the enantiodiscrimination of several negatively charged and zwitterionic model racemates. The substituent-dependent enantiomer migration order reversal of dansylated-valine using PIP-β-CD contrary to PYP-β-CD, MO-β-CD and PIPA-β-CD was also studied by ¹H- and 2D ROESY NMR experiments. Full article

Superoxide radical anion (O₂^•−) and its derivatives regulate numerous physiological and pathological processes, which are extensively studied. The aim of our work was to utilize KO₂ as a source of O₂^•− and the electron paramagnetic resonance (EPR) spin trapping 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) technique for the preparation of ^•BMPO-OOH and/or ^•BMPO-OH radicals in water solution without DMSO. The method distinguishes the interactions of various compounds with ^•BMPO-OOH and/or ^•BMPO-OH radicals over time. Here, we show that the addition of a buffered BMPO-HCl mixture to powdered KO₂ formed relatively stable ^•BMPO-OOH and ^•BMPO-OH radicals and H₂O₂, where the ^•BMPO-OOH/OH ratio depended on the pH. At a final pH of ~6.5–8.0, the concentration of ^•BMPO-OOH radicals was ≥20 times higher than that of ^•BMPO-OH, whereas at pH 9.0–10.0, the ^•BMPO-OH radicals prevailed. The ^•BMPO-OOH/OH radicals effectively cleaved the plasmid DNA. H₂S decreased the concentration of ^•BMPO-OOH/OH radicals, whereas the selenium derivatives 1-methyl-4-(3-(phenylselanyl) propyl) piperazine and 1-methyl-4-(4-(phenylselanyl) butyl) piperazine increased the proportion of ^•BMPO-OH over the ^•BMPO-OOH radicals. In conclusion, the presented approach of using KO₂ as a source of O₂^•−/H₂O₂ and EPR spin trap BMPO for the preparation of ^•BMPO-OOH/OH radicals in a physiological solution could be useful to study the biological effects of radicals and their interactions with compounds. Full article