The data on the synthesis of N-aminomorpholine hydrazones are presented. It is shown that the interaction of N-aminomorpholine with functionally substituted benzaldehydes and 4-pyridinaldehyde in isopropyl alcohol leads to the formation of corresponding hydrazones. The structure of the synthesized compounds was studied by 1H and 13C NMR spectroscopy methods, including the COSY (1H-1H), HMQC (1H-13C) and HMBC (1H-13C) methodologies. The values of chemical shifts, multiplicity, and integral intensity of 1H and 13C signals in one-dimensional NMR spectra were determined. The COSY (1H-1H), HMQC (1H-13C), and HMBC (1H-13C) results revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The antiviral, cytotoxic, and antimicrobial activity of some synthesized hydrazones were investigated. It is shown that 2-((morpholinoimino)methyl)benzoic acid has a pronounced viral inhibitory property, comparable in its activity to commercial drugs Tamiflu and Remantadine. A docking study was performed using the influenza virus protein models (1930 Swine H1 Hemagglutinin and Neuraminidase of 1918 H1N1 strain). The potential binding sites that are complementary with 2-((morpholinoimino)methyl)benzoic acid were found.

In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone β-carboline analogues 9a-o and 10a-o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target β-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure-activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone β-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of β-carboline analogues as new potential antifungal agents.

In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9-20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9-20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9-20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9-20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9-20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59-176.70 μM for the A549 cell line and 27.70-170.30 μM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 μM against A549 cell line and IC50 = 27.70 μM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 μM against A549 cell line and IC50 = 18.01 μM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski\'s rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.

UNASSIGNED: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage.
UNASSIGNED: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023.
UNASSIGNED: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred.
UNASSIGNED: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory.
UNASSIGNED: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.

In an effort to develop new and effective therapeutic agents for Alzheimer\'s disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Thin-layer chromatography (TLC) hyphenated to bioassays is a modern tool used for discovery of biologically active compounds from complex mixtures. The first bioautographic assay for detecting laccase inhibitors on a TLC plate was developed in this study. The on-plate reaction of laccase with colourless ABTS that renders the blue ABTS∙+ radical was optimised. Combination of the enzymatic TLC-assay with a control TLC-assay, wherein ABTS∙+ radical is chemically generated and then applied on the TLC, allowed to differentiate between the pure laccase inhibitor sodium azide and radical scavengers such as gallic and kojic acids. The limit of detection and quantification for the method were 54.9 and 166 ng of sodium azide respectively. The methodology was applied successfully to a recently discovered laccase inhibitor chemotype: hydrazones. A model hydrazone was compared with several hydrazones synthesized for this study. For the first time, laccase inhibitors separated on a TLC plate can be detected individually.

BACKGROUND: Hydrazones have been studied for a myriad of chemical and physiochemical properties, such as sensors, chelators and numerous biological activities. Experimental data indicates that hydrazones are unstable under cathodic potentials irrespective of the solvent. The single electron reduction of hydrazones to produce radical anions result in unstable species that cleaves at the N-N bond in a heterolytic manner. The literature has proposed a mechanism favouring the radical on the imine moiety, however in this study DFT calculations suggest the radical on the amine product is more likely upon bond cleavage. This has implications on electrochemical mechanisms, and the active molecule in biological studies viz the method of delivery to target areas.
METHODS: Density functional theory calculations were carried out using the GAMESS software package. The structures were optimized in the gas phase (B3LYP/6-31G(d,p)) as indicated by the absence of imaginary frequencies in the Hessian, and in CH3CN (B3LYP/6-31G(d,p)/SMD) with the Pople polarization functions. As a comparison, selected pathways were fully optimized using PBE0/6-31G(d,p) and PBE0/6-31G(d,p)/SMD for gas phase and CH3CN, respectively with the Pople polarization functions. The values were not significantly different (< 5% difference). As such only the B3LYP is evaluation is discussed.

Efforts in researching the efficient anti-tumor properties of three novel arene ruthenium(II) complexes incorporating thiophene-based aroylhydrazone ligands have been undertaken. The complexes\' elemental composition was [(η6-p-cymene)Ru(L)Cl]. They were comprehensively characterized through elemental and spectroscopic analyses (FT-IR, UV-vis, NMR, and HR-MS). Single crystal X-ray diffraction studies revealed a pseudo-octahedral geometry with bidentate coordination of the ligands in a representative complex. The in vitro assessment of the complexes\' cancer cell growth inhibition was conducted using the MTT assay against A549 (human lung carcinoma), HeLa (human cervical carcinoma), HuH-7 (hepatocellular carcinoma), and NIH-3T3 (mouse fibroblast non-cancerous cell line). Results indicated significant cytotoxicity across all cancer cell lines, with IC50 concentrations of complex 2 being 6.8 μM for A549, 11.6 μM for HeLa, and 9.4 μM for HuH-7, compared to cisplatin with IC50 values of 18.9 μM, 17.68 μM, and 24 μM respectively. Notably, complex 2 demonstrated particularly promising cytotoxicity against all tested cancerous cell lines. Fluorescent staining analysis such as acridine orange/ethidium bromide (AO-EB) and HOECHST 33342 revealed cell death mechanisms involving membrane disintegration and nuclear condensation following treatment with complex 2. Further studies were conducted to measure reactive oxygen species (ROS) levels using the dichlorodihydrofluorescein diacetate (DCFH-DA) assay, and mitochondrial membrane potential (MMP) was assessed using the JC-1 dye assay. These studies demonstrated that complex 2 increased ROS levels, decreased membrane potential, and promoted mitochondrial dysfunction-mediated cell death pathways. Additionally, flow cytometry analysis, utilizing dual staining of Annexin V-FITC and propidium iodide (PI), was employed to quantitatively study apoptosis induction.

Adult neurogenesis involves the generation of functional neurons from neural progenitor cells, which have the potential to complement and restore damaged neurons and neural circuits. Therefore, the development of drugs that stimulate neurogenesis represents a promising strategy in stem cell therapy and neural regeneration, greatly facilitating the reconstruction of neural circuits in cases of neurodegeneration and brain injury. Our study reveals that compound A5, previously designed and synthesized by our team, exhibits remarkable neuritogenic activities, effectively inducing neurogenesis in neural stem/progenitor cells (NSPCs). Subsequently, transcriptome analysis using high-throughput Illumina RNA-seq technology was performed to further elucidate the underlying molecular mechanisms by which Compound A5 promotes neurogenesis. Notably, comparative transcriptome analysis showed that the up-regulated genes were mainly associated with neurogenesis, and the down-regulated genes were mainly concerned with cell cycle progression. Furthermore, we confirmed that Compound A5 significantly affected the expression of transcription factors related to neurogenesis and cell cycle regulatory proteins. Collectively, these findings identify a new compound with neurogenic activity and may provide insights into drug discovery for neural repair and regeneration.