ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

An allosteric inhibitor of the PhoQ histidine kinase with therapeutic potential against Salmonella infection.

BACKGROUND: The upsurge of antimicrobial resistance demands innovative strategies to fight bacterial infections. With traditional antibiotics becoming less effective, anti-virulence agents or pathoblockers, arise as an alternative approach that seeks to disarm pathogens without affecting their viability, thereby reducing selective pressure for the emergence of resistance mechanisms. OBJECTIVES: To elucidate the mechanism of action of compound N'-(thiophen-2-ylmethylene)benzohydrazide (A16B1), a potent synthetic hydrazone inhibitor against the Salmonella PhoP/PhoQ system, essential for virulence. MATERIALS AND METHODS: The measurement of the activity of PhoP/PhoQ-dependent and -independent reporter genes was used to evaluate the specificity of A16B1 to the PhoP regulon. Autokinase activity assays with either the native or truncated versions of PhoQ were used to dissect the A16B1 mechanism of action. The effect of A16B1 on Salmonella intramacrophage replication was assessed using the gentamicin protection assay. The checkerboard assay approach was used to analyse potentiation effects of colistin with the hydrazone. The Galleria mellonella infection model was chosen to evaluate A16B1 as an in vivo therapy against Salmonella. RESULTS: A16B1 repressed the Salmonella PhoP/PhoQ system activity, specifically targeting PhoQ within the second transmembrane region. A16B1 demonstrates synergy with the antimicrobial peptide colistin, reduces the intramacrophage proliferation of Salmonella without being cytotoxic and enhances the survival of G. mellonella larvae systemically infected with Salmonella. CONCLUSIONS: A16B1 selectively inhibits the activity of the Salmonella PhoP/PhoQ system through a novel inhibitory mechanism, representing a promising synthetic hydrazone compound with the potential to function as a Salmonella pathoblocker. This offers innovative prospects for combating Salmonella infections while mitigating the risk of antimicrobial resistance emergence.

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research.

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

Synthesis, SARS-CoV-2 main protease inhibition, molecular docking and in silico ADME studies of furanochromene-quinoline hydrazone derivatives.

Seven furanochromene-quinoline derivatives containing a hydrazone linker were synthesized by condensing a furanochromene hydrazide with quinoline 2-, 3-, 4-, 5-, 6-, and 8-carbaldehydes, including 8-hydroxyquinoline-2-carbaldehye. Structure-activity correlations were investigated to determine the influence of the location of the hydrazone linker on the quinoline unit on SARS-CoV-2 Mpro enzyme inhibition. The 3-, 5-, 6- and 8-substituted derivatives showed moderate inhibition of SARS-CoV-2 Mpro with IC50 values ranging from 16 to 44 µM. Additionally, all of the derivatives showed strong interaction with the SARS-CoV-2 Mpro substrate binding pocket, with docking energy scores ranging from -8.0 to -8.5 kcal/mol. These values are comparable to that of N3 peptide (-8.1 kcal/mol) and more favorable than GC-373 (-7.6 kcal/mol) and ML-188 (-7.5 kcal/mol), all of which are known SARS-CoV-2 Mpro inhibitors. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) profiles indicate that the derivatives have good drug-likeness properties. Overall, this study highlights the potential of the furanochromene-quinoline hydrazone scaffold as a SARS-CoV-2 Mpro inhibitor.

Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum.

In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.

Discovery andsynthesis of novel benzoylhydrazone neuraminidase inhibitors.

Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC50 = 0.13 µM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC50 = 0.44 µM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.

Novel hydrazones derived from anthranilic acid as potent cholinesterases and α-glycosidase inhibitors: Synthesis, characterization, and biological effects.

N-substitued anthranilic acid derivatives are commonly found in the structure of many biologically active molecules. In this study, new members of hydrazones derived from anthranilic acid (1-15) were synthesized and investigated their effect on some metabolic enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). Results indicated that all the molecules exhibited potent inhibitory effects against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of compounds for AChE, BChE, and α-Gly enzymes were obtained in the ranges 66.36 ± 8.30-153.82 ± 13.41, 52.68 ± 6.38-113.86, and 2.13 ± 0.25-2.84 nM, respectively. The molecular docking study was performed for the most active compounds to the determination of ligand-enzyme interactions. Binding affinities of the most active compound were found at the range of -9.70 to -9.00 kcal/mol for AChE, -11.60 to -10.60 kcal/mol for BChE, and -10.30 to -9.30 kcal/mol for α-Gly. Molecular docking simulations showed that the novel compounds had preferential interaction with AChE, BChE, and α-Gly. Drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyzes of all synthesized compounds (1-15) were estimated and their toxic properties were evaluated as well as their therapeutic properties. Moreover, molecular dynamics simulations were carried out to understand the accuracy of the most potent derivatives of docking studies.

Phenylhydrazone Alkaloids from the Deep-Sea Cold Seep Derived Fungus Talaromyces amestolkiae HDN21-0307.

Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A-D (1-4) were isolated from the deep-sea cold seep derived fungus Talaromyces amestolkiae HDN21-0307 using the one strain-many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Talarohydrazone A (1) possessed an unusual skeleton combining 2,4-pyridinedione and phenylhydrazone. Talarohydrazone B (2) represents the first natural phenylhydrazone-bearing azadophilone. Bioactivity evaluation revealed that compound 1 exhibited cytotoxic activity against NCI-H446 cells with an IC50 value of 4.1 µM. In addition, compound 1 displayed weak antibacterial activity toward Staphylococcus aureus with an MIC value of 32 µg/mL.

Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson's disease.

Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.

Design, synthesis and mechanistic studies of novel arylformylhydrazone butylphenyltin complexes as potential anticancer agents.

Many diorganotin complexes with various alkyl groups exhibit excellent in vitro anticancer activity. However, most diorganotin is the same alkyl group, and the asymmetric alkyl R group has been rarely reported. Hence, in this paper, twenty butylphenyl mixed dialkyltin arylformylhydrazone complexes have been synthesized by microwave "one-pot" reaction with arylformylhydrazine, substituted α-keto acid or its sodium salt and butylphenyltin dichloride. The crystal structures of nine complexes were determined, indicating that the complexes C1, C2, C11, C12, and C16 âˆ¼ C19 possessed a central symmetric structure of a dinuclear Sn2O2 tetrahedral ring; while the complex C9 is a trinuclear tin-oxygen cluster with a 6-membered ring encased in a 12-membered macrocyclic structure. The inhibiting activity of complexes was tested against the human cell lines NCI-H460, MCF-7, HepG2, Huh-7 and HL-7702. Complex C2 demonstrated the optimal inhibitory effect on HepG2 cells, with an IC50 value of 0.82 ± 0.03 µM. Cellular biology experiments revealed that complex C2 could induce apoptosis and G2/M phase cell cycle arrest in HepG2 and Huh-7 cells. The complex also caused the collapse of the mitochondrial membrane potential and increased intracellular reactive oxygen species in HepG2 and Huh-7 cells. Western blot analysis further clarified that complex C2 could induce cell apoptosis through the mitochondrial pathway along with the release of reactive oxygen species.

Novel isoniazid-hydrazone derivatives induce cell growth inhibition, cell cycle arrest and apoptosis via mitochondria-dependent caspase activation and PI3K/AKT inhibition.

In this study, seven isoniazid-hydrazone derivatives (3a-g) were synthesized and their structures elucidated by chromatographic techniques, and then the antiproliferative effects of these compounds on various cancer cells were tested. The advanced anticancer mechanism of the most potent compound was then investigated. Antiproliferative activities of the synthesized compounds were evaluated on human breast cancer MCF-7, lung cancer A-549, colon cancer HT-29, and non-cancerous mouse fibroblast 3T3-L1 cell lines by XTT assay. Flow cytometry analysis were carried out to determine cell cycle distribution, apoptosis, mitochondrial membrane potential, multi-caspase activity, and expression of PI3K/AKT signaling pathway. The XTT results showed that all the title molecules displayed cytotoxic activity at varying strengths in different dose ranges, and among them, the strongest cytotoxic effect and high selectivity were exerted by 3d against MCF-7 cells with the IC50 value of 11.35 µM and selectivity index of 8.65. Flow cytometry results revealed that compound 3d induced apoptosis through mitochondrial membrane disruption and multi-caspase activation in MCF-7 cells. It also inhibited the cell proliferation via inhibition of expression of PI3K/AKT and arrested the cell cycle at G0/G1 phase. In conclusion, all these data disclosed that among the synthesized compounds, 3d is notable for in vivo anticancer studies.

In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes.

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

Molecular insights on Eltrombopag: potential mitogen stimulants, angiogenesis, and therapeutic radioprotectant through TPO-R activation.

The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.

What is the context?● Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.● Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?● This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).● The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.● The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.● The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG's molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.

Hydrazone chemistry-mediated CRISPR/Cas12a system for bacterial analysis.

In this study, a hydrazone chemistry-mediated clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 12a (Cas12a) system has been proposed for the fist time and constructed. In our system, hydrazone chemistry is designed and employed to accelerate the formation of a whole activation strand by taking advantage of the proximity effect induced by complementary base pairing, thus activating the CRISPR/Cas12a system quickly and efficiently. Moreover, the introduction of hydrazone chemistry can improve the specificity of the CRISPR/Cas12a system, allowing it to effectively distinguish single-base mismatches. The established system has been further applied to analyze Pseudomonas aeruginosa by specific recognition of the probe strand with a characteristic fragment in 16S rDNA to release the hydrazine group-modified activation strand. The method shows a wide linear range from 3.8 × 102 colony-forming units (CFU)/ml to 3.8 × 106 CFU/ml, with the lowest detection limit of 24 CFU/ml. Therefore, the introduction of hydrazone chemistry may also broaden the application of the CRISPR/Cas12a system.

Cardiotoxicity and ROS Protection Assessment of three Structure-Related N-Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases.

The senescence process is associated with accumulated oxidative damage and increased metal concentration in the heart and brain. Besides, abnormal metal-protein interactions have also been linked with the development of several conditions, including Alzheimer's and Parkinson's diseases. Over the years we have described a series of structure-related compounds with different activities towards models of such diseases. In this work, we evaluated the potential of three N-acylhydrazones (INHHQ: 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone, HPCIH: pyridine-2-carboxaldehyde isonicotinoyl hydrazone and X1INH: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone) to prevent oxidative stress in cellular models, with the dual intent of being active on this pathway and also to confirm their lack of cardiotoxicity as an important step in the drug development process, especially considering that the target population often presents cardiovascular comorbidity. The 8-hydroxyquinoline-contaning compound, INHHQ, exhibits a significant cardioprotective effect against hydrogen peroxide and a robust antioxidant activity. However, this compound is the most toxic to the studied cell models and seems to induce oxidative damage on its own. Interestingly, although not possessing a phenol group in its structure, the new-generation 1-methylimidazole derivative X1INH showed a cardioprotective tendency towards H9c2 cells, demonstrating the importance of attaining a compromise between activity and intrinsic cytotoxicity when developing a drug candidate.

Development of Novel Indazolyl-Acyl Hydrazones as Antioxidant and Anticancer Agents that Target VEGFR-2 in Human Breast Cancer Cells.

The increased expression of VEGFR-2 in a variety of cancer cells promotes a cascade of cellular responses that improve cell survival, growth, and proliferation. Heterocycles are common structural elements in medicinal chemistry and commercially available medications that target several biological pathways and induce cell death in cancer cells. Herein, the evaluation of indazolyl-acyl hydrazones as antioxidant and anticancer agents is reported. Compounds 4e and 4j showed inhibitory activity in free radical scavenging assays (DPPH and FRPA). The titled compounds were employed in cell viability studies using MCF-7 cells, and it was observed that compounds 4f and 4j exhibited IC50 values 15.83 µM and 5.72 µM, respectively. In silico docking revealed the favorable binding energies of -7.30 kcal/mol and -8.04 kcal/mol for these compounds towards Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), respectively. In conclusion, compounds with antioxidant activity and that target VEGFR-2 in breast cancer cells are reported.

Synthesis and Antifungal Activity of Coumarin Derivatives Containing Hydrazone Moiety.

Plant disease control mainly relies on pesticides. In this study, a series of coumarin derivatives containing hydrazone moiety were designed and synthesized. The synthesized compounds were characterized and used to evaluate the antifungal activity against four pathogens, Botrytis cinerea, Alternaria solani, Fusarium oxysporum, and Alternaria alternata. The results showed that the inhibition rate of some compounds at 100 µg/mL in 96 hours reached around 70 % against A. alternata, higher than that of the positive control. The corresponding EC50 values were found at around 30 µg/mL. Finally, the compound 3 b was screened out with the lowest EC50 value (19.49 µg/mL). The analysis of SEM and TEM confirmed that the compound 3 b can obviously damage the morphological structure of hyphae, resulting in the depletion of the cells by the destruction of morphological matrix and leakage of contents. RNA sequencing showed that compounds 3 b mainly affected the pentose phosphate pathway, which caused to destroy the layer of mitochondrial structure. Molecular docking showed that compounds 3 b fitted the binding pocket of yeast transketolase and interacted with lysine at the hydrazone structure. Our results suggested that the introduction of hydrazone was an effective strategy for the design of novel bioactive compounds.

Design, Synthesis and Antifungal Activity of Nootkatone Derivatives Containing Acylhydrazone and Oxime Ester.

In an attempt to search for new natural products-based antifungal agents, fifty-three nootkatone derivatives were designed, synthesized, and evaluated for their antifungal activity against Phytophthora parasitica var nicotianae, Fusarium oxysporum, Fusarium graminearum and Phomopsis sp. by the mycelium growth rate method. Nootkatone derivatives N17 exhibited good inhibitory activity against Phomopsis. sp. with EC50 values of 2.02 µM. The control effect of N17 against Phomopsis. sp. on kiwifruit showed that N17 exhibited a good curative effect in reducing kiwifruit rot at the concentration of 202 µM(100×EC50 ), with the curative effect of 41.11 %, which was better than commercial control of pyrimethanil at the concentration of 13437 µM(100×EC50 ) with the curative effect of 38.65 %. Phomopsis. sp. mycelium treated with N17 showed irregular surface collapse and shrinkage, and the cell membrane crinkled irregularly, vacuoles expanded significantly, mitochondria contracted, and organelles partially swollen by the SEM and TEM detected. Preliminary pharmacological experiments show that N17 exerted antifungal effects by altering release of cellular contents, and altering cell membrane permeability and integrity. The cytotoxicity test demonstrated that N17 showed almost no toxicity to K562 cells. The presented results implied that N17 may be as a potential antifungal agents for developing more efficient fungicides to control Phomopsis sp.

Synthesis of 3-hydroxy-2-naphthohydrazide-based hydrazones and their implications in diabetic management via in vitro and in silico approaches.

Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, "α-glucosidase." Several approaches including fourier transform infrared, 1 H NMR, and 13 C NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a-3p displayed more effective inhibitory activities against α-glucosidase with IC50 in a range of 2.80-29.66 µM as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 ± 0.03 µM, followed by 3i (IC50 = 4.13 ± 0.06 µM), 3f (IC50 = 5.18 ± 0.10 µM), 3c (IC50 = 5.42 ± 0.11 µM), 3g (IC50 = 6.17 ± 0.15 µM), 3d (IC50 = 6.76 ± 0.20 µM), 3a (IC50 = 9.59 ± 0.14 µM), and 3n (IC50 = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with Ki value = 4.76 ± 0.0068 µM. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene-ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the α-glucosidase enzyme.

New 2-nitroimidazole-N-acylhydrazones, analogs of benznidazole, as anti-Trypanosoma cruzi agents.

Chagas disease is a neglected tropical parasitic disease caused by the protozoan Trypanosoma cruzi. Worldwide, an estimated 8 million people are infected with T. cruzi, causing more than 10,000 deaths per year. Currently, only two drugs, nifurtimox and benznidazole (BNZ), are approved for its treatment. However, both are ineffective during the chronic phase, show toxicity, and produce serious side effects. This work aimed to obtain and evaluate novel 2-nitroimidazole-N-acylhydrazone derivatives analogous to BNZ. The design of these compounds used the two important pharmacophoric subunits of the BNZ prototype, the 2-nitroimidazole nucleus and the benzene ring, and the bioisosterism among the amide group of BNZ and N-acylhydrazone. The 27 compounds were obtained by a three-step route in 57%-98% yields. The biological results demonstrated the potential of this new class of compounds, since eight compounds were potent and selective in the in vitro assay against T. cruzi amastigotes and trypomastigotes using a drug-susceptible strain of T. cruzi (Tulahuen) (IC50 = 4.3-6.25 µM) and proved to be highly selective with low cytotoxicity on L929 cells. The type I nitroreductase (TcNTR) assay suggests that the new compounds may act as substrates for this enzyme.