Exploring the Antiproliferative Potential of Morpholine‐Functionalized Aurones: Design, Synthesis, SAR, DFT, Hirshfeld Surface, 3D Energy Frameworks and Molecular Docking Analysis

ChemistrySelect, Год журнала: 2024, Номер 9(20)

Опубликована: Май 22, 2024

Abstract In quest of generating a diverse array potential cytotoxic candidates through molecular hybridization approach, herein we have designed library forty‐one morpholine‐functionalized aurones 7(a–ao), each with distinct substitution pattern. These were obtained by reacting 6‐hydroxyaurones, 4‐(2‐chloroethyl)morpholine hydrochloride, characterized various spectroscopic techniques including single crystal XRD (7b) and in‐vitro screened for their antiproliferative against human gastric adenocarcinoma (AGS) cells. Most the synthesized compounds exhibited excellent results. Twenty analogs found to better than reference drug Leucovorin analog 7j emerged as most potent IC 50 =5.98 μM nearly one fifth standard (IC =30.8 μM). This library, consisting twenty three novel eighteen reported aurones, bearing pattern, further helped in making concrete structure‐activity relationship potential. Additionally, in‐silico docking, Hirshfeld surface analysis two dimensional fingerprint plots also studied understand interactions structural aspects. Further computational investigations these conducted using DFT/B3LYP method, determination HOMO LUMO energy values well calculation chemical softness, hardness, electronegativity electrophilic index etc.

Язык: Английский

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In Silico and In Vitro Studies of the Approved Antibiotic Ceftaroline Fosamil and Its Metabolites as Inhibitors of SARS-CoV-2 Replication

Viruses, Год журнала: 2025, Номер 17(4), С. 491 - 491

Опубликована: Март 28, 2025

The SARS-CoV-2 proteases Mpro and PLpro are critical targets for antiviral drug development the treatment of COVID-19. 1,2,4-thiadiazole functional group is an inhibitor cysteine proteases, such as papain cathepsins. This chemical moiety also present in ceftaroline fosamil (CF), FDA-approved fifth-generation cephalosporin antibiotic. study investigates interactions between CF, its primary metabolites (M1 dephosphorylated CF M2 opened β-lactam ring) derivatives (protonated M1H M2H), open rings (open-M1H open-M2H) with evaluates CF’s effects on vitro viral replication. In silico analyses (molecular docking molecular dynamics (MD) simulations) demonstrated that potential inhibitors Mpro. Docking analysis indicated majority ligands were more stable than PLpro; however, biochemical preferred target CF. inhibited replication human Calu-3 cell model at submicromolar concentrations when added to culture medium 12 h. Our results suggest should be evaluated a repurposing agent COVID-19, considering not only but other relevant cellular pathways. Additionally, reactivity sulfur warrants further exploration protease inhibitors.

Язык: Английский

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Nanotechnology-Driven Strategy Against SARS-CoV-2: Pluronic F127-Based Nanomicelles with or Without Atazanavir Reduce Viral Replication in Calu-3 Cells

Viruses, Год журнала: 2025, Номер 17(4), С. 518 - 518

Опубликована: Апрель 1, 2025

Despite extensive efforts, no highly effective antiviral molecule exists for treating moderate and severe COVID-19. Nanotechnology has emerged as a promising approach developing novel drug delivery systems to enhance efficacy. Among these, polymeric nanomicelles improve the solubility, bioavailability, cellular uptake of therapeutic agents. In this study, Pluronic F127-based were developed evaluated their activity against SARS-CoV-2. The nanomicelles, formulated using direct dissolution method, exhibited an average size 37.4 ± 8.01 nm polydispersity index (PDI) 0.427 0.01. Their efficacy was assessed in SARS-CoV-2-infected Vero E6 Calu-3 cell models, where treatment with 1:2 dilution inhibited viral replication by more than 90%. Cytotoxicity assays confirmed non-toxic both lines after 72 h. cells (human type II pneumocyte model), containing atazanavir (ATV) significantly reduced replication, even under high MOI (2) 48 h, while also preventing IL-6 upregulation. To investigate mechanism, pretreatment showed inhibitory effect. However, pre-exposure led significant reduction (>85% >75% 1:4 dilutions, respectively), transmission electron microscopy. These findings highlight nanotechnology-driven strategy SARS-CoV-2, reinforcing potential future therapies.

Язык: Английский

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α-Aryl-α-tetralone Derivatives and Fluorinated Analogs: Synthesis and Antiproliferative Evaluation on Colorectal Cancer via Inhibition of Wnt/β-Catenin Signaling

Journal of Molecular Structure, Год журнала: 2025, Номер unknown, С. 142251 - 142251

Опубликована: Апрель 1, 2025

Язык: Английский

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Antiviral Effect of 5′-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection

Molecules, Год журнала: 2023, Номер 28(18), С. 6696 - 6696

Опубликована: Сен. 19, 2023

The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and chalcogen atoms can increase bioactivity reduce toxicity AZT has directed our search for discovery novel potential anti-coronavirus compounds. Here, antiviral activity selenium tellurium containing derivatives in human type II pneumocytes cell model (Calu-3) monkey kidney cells (Vero E6) infected with SARS-CoV-2, their toxic effects on these cells, was evaluated. Cell viability analysis revealed organoselenium (R3a-R3e) showed lower cytotoxicity than organotellurium (R3f, R3n-R3q), CC50 ≥ 100 µM. R3b R3e were particularly noteworthy inhibiting viral replication both models better selectivity index. In Vero E6, EC50 values 2.97 ± 0.62 µM 1.99 0.42 µM, respectively, while Calu-3, concentrations 3.82 1.42 1.92 0.43 (24 h treatment) 1.33 0.35 2.31 0.54 (48 h) observed, respectively. molecular docking calculations carried out to main protease (Mpro), papain-like (PLpro), RdRp following non-competitive, competitive, allosteric inhibitory approaches. silico results suggested is a non-competitive inhibitor RdRp, interacting cavity located palm region. Overall, cell-based indicated chalcogen-zidovudine more potent compounds play an important role, expanding knowledge about promising therapeutic capacity against COVID-19.

Язык: Английский

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Myrtucommulones and Related Acylphloroglucinols from Myrtaceae as a Promising Source of Multitarget SARS-CoV-2 Cycle Inhibitors

Pharmaceuticals, Год журнала: 2024, Номер 17(4), С. 436 - 436

Опубликована: Март 28, 2024

The LABEXTRACT plant extract bank, featuring diverse members of the Myrtaceae family from Brazilian hot spot regions, provides a promising avenue for bioprospection. Given pivotal roles Spike protein and 3CLpro PLpro proteases in SARS-CoV-2 infection, this study delves into correlations between species Atlantic Forest these targets, as well an antiviral activity through both vitro silico analyses. results uncovered notable inhibitory effects, with Eugenia prasina E. mosenii standing out, while proved to be multitarget, presenting inhibition values above 72% three targets analyzed. All extracts inhibited viral replication Calu-3 cells (EC50 was lower than 8.3 µg·mL−1). Chemometric analyses, LC-MS/MS, encompassing prediction models molecular networking, identified potential active compounds, such myrtucommulones, described literature their activity. Docking analyses showed that one undescribed myrtucommulone (m/z 841 [M − H]−) had higher fitness score when interacting study, including ACE2, Spike, SARS-CoV-2. Also, concludes extracts, particularly prasina, exhibit effects against crucial stages infection. Compounds like myrtucommulones emerge anti-SARS-CoV-2 agents, warranting further exploration.

Язык: Английский

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How many organic small molecules might be used to treat COVID-19? From natural products to synthetic agents

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 278, С. 116788 - 116788

Опубликована: Сен. 4, 2024

Язык: Английский

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Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights

Viruses, Год журнала: 2024, Номер 16(11), С. 1768 - 1768

Опубликована: Ноя. 13, 2024

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity mortality over time. The COVID-19 has underscored the urgent need for development discovery of new, potent antiviral agents. In this study, we present synthesis anti-SARS-CoV-2 activity a series benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on inhibition SARS-CoV-2 main protease (Mpro) papain-like (PLpro) have used enzymatic Notably, 4a 4b showed Mpro with IC50 0.11 ± 0.05 0.37 µM, respectively. Furthermore, silico molecular docking, physicochemical, pharmacokinetic studies were conducted validate mechanism assess bioavailability. Compound was selected preliminary drug-likeness analysis vivo pharmacokinetics investigations, which yielded promising corroborated vitro findings, reinforcing its potential as an lead compound.

Язык: Английский

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Design, Synthesis and Evaluation of Aurone and Indanone Derivatives as Novel Antibacterial Agents

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Сен. 4, 2023

Abstract Aurones and indanones were proved to be potential antibacterial agents in our recent work. Based on strategy of bioisosterism diene insertion, a series aurone indanone derivatives designed synthesized, then submitted the activity evaluation C. albicans, E. coli S. aureus . According results, nineteen thirty synthesized compounds had inhibitory against at least one bacterium. The minimum value MIC was 62.5 µM ( A2 , B1 B3 B4 B8 C6 D1 D2 ) MBC ). In addition, molecular docking ADMET prediction also applied possible binding mode druggability active compounds. Our research once again demonstrated that are good scaffolds for development agents, especially bacterial.

Язык: Английский

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Design, synthesis and evaluation of aurone and indanone derivatives as novel antitumor agents

Medicinal Chemistry Research, Год журнала: 2023, Номер 33(1), С. 201 - 220

Опубликована: Дек. 20, 2023

Язык: Английский

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