Identification of sulphonamide-tethered N -((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: July 11, 2023

SARS-CoV-2 pandemic in the end of 2019 led to profound consequences on global health and economy. Till producing successful vaccination strategies, healthcare sectors suffered from lack effective therapeutic agents that could control spread infection. Thus, academia pharmaceutical sector prioritise antiviral drug discovery. Here, we exploited previous reports highlighting anti-SARS-CoV-2 activities isatin-based molecules develop novel triazolo-isatins for inhibiting main protease (Mpro) virus, a crucial enzyme its replication host cells. Particularly, sulphonamide 6b showed promising inhibitory activity with an IC50= 0.249 µM. Additionally, inhibited viral cell proliferation IC50 4.33 µg/ml, was non-toxic VERO-E6 cells (CC50 = 564.74 µg/ml) displaying selectivity index 130.4. In silico analysis disclosed ability interact key residues active site, supporting obtained vitro findings.

Language: Английский

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Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)/ IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 149, P. 107483 - 107483

Published: May 21, 2024

Language: Английский

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Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 67(1), P. 492 - 512

Published: Dec. 20, 2023

Herein, modifications to the previously reported BIBR1591 were conducted obtain bioisosteric candidates with improved activities. The % inhibition of newly afforded against telomerase target was investigated. Notably, 6f achieved superior (63.14%) compared BIBR1532 and (69.64 51.58%, respectively). In addition, 8a 8b showed comparable promising 58.65 55.57%, respectively, which recorded be frontier that BIBR1591. 6f, 8a, tested five cancer cell lines related lung liver subtypes. Moreover, examined on both cycle progression apoptosis induction in HuH7 cells. Furthermore, vivo antitumor activity further assessed female mice solid Ehrlich carcinoma. molecular docking dynamics simulations carried out. Collectively, could considered potential new inhibitors subjected investigation and/or optimization.

Language: Английский

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Metabolites profiling, in-vitro and molecular docking studies of five legume seeds for Alzheimer’s disease

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 23, 2024

Abstract Even though legumes are valuable medicinal plants with edible seeds that extensively consumed worldwide, there is little information available on the metabolic variations between different dietary beans and their influence as potential anti-cholinesterase agents. High-resolution liquid chromatography coupled mass spectrometry in positive negative ionization modes combined multivariate analysis were used to explore differences profiles of five commonly seeds, fava bean, black-eyed pea, kidney red lentil, chickpea. A total 139 metabolites from various classes identified including saponins, alkaloids, phenolic acids, iridoids, terpenes. Chickpea showed highest antioxidant effects, followed by beans. Supervised unsupervised chemometric determined species could be distinguished discriminatory metabolites. The major pathways also studied. Glycerophospholipid metabolism was most significantly enriched KEGG pathway. Pearson’s correlation pinpointed 18 positively correlated activity. Molecular docking biomarkers active sites acetyl- butyryl-cholinesterase enzymes revealed promising binding scores, validating results. present study will add metabolomic nutritional value advocate inclusion anti-Alzheimer’s formulations.

Language: Английский

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Luteolin loaded PEGylated cerosomes: a novel treatment for MRSA skin infections

BMC Microbiology, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 31, 2025

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections which, due to the spread antimicrobial resistance, have become increasingly serious. Bacterial infection affects barrier function causing depletion ceramide content in stratum corneum (SC) epidermis. In study reported herein, luteolin (LUT) naturally-occurring flavonoid was incorporated PEGylated cerosomes (PCs) boost its antibacterial action as topical application. The opimal formulation surface-modified lipidic vesicles chosen with aid 2 3 full factorial design. effectiveness optimal LUT which developed evaluated using several MRSA strains both vitro vivo studies. Results A design employed for preparation optimum PC formulation, designated herein F5. comparative release revealed superiority F5 over suspension solubilizing releasing after 24 h, higher percentage 78.1 ± 1.8% compared only 18.3 2.1% suspension. When tested against strains, showed activity that than suspension, having MIC value 187.5 µg/mL versus 1500 µg/mL. addition enhanced anti-virulence terms antibiofilm formation (with % inhibition ranging from 45 99% at 0.5 × 0.25 MICs, where had range 1 45%), anti-pigment production, anti-α-hemolysin were also observed. Moreover, affected cell wall integrity confirmed by transmission electron microscopy (TEM). Scanning (SEM) verified effect on bacterial biofilm formation, showing reduction cellular adhesion disruption biofilm, factors greatly contribute pathogenesis antibiotic resistance. negative control groups, resulted reducing load murine model. Conclusions are potential new potent defense agents infections, demonstrating promising therapeutic capabilities.

Language: Английский

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Exploring chromone‐2‐carboxamide derivatives for triple‐negative breast cancer targeting EGFR, FGFR3, and VEGF pathways: Design, synthesis, and preclinical insights

Drug Development Research, Journal Year: 2024, Volume and Issue: 85(5)

Published: July 1, 2024

Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized evaluated for their in vitro anticancer activity against 15 human lines. Among the tested lines, MDA-MB-231, triple-negative breast line, was found to be most sensitive, where N-(2-furylmethylene) (15) α-methylated N-benzyl (17) demonstrated highest growth inhibition with GI

Language: Английский

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The Influence of the AgNPs Ligand on the Antiviral Activity Against HSV-2

International Journal of Nanomedicine, Journal Year: 2025, Volume and Issue: Volume 20, P. 2659 - 2671

Published: March 1, 2025

In this paper, we discuss the influence of ligand type present on surface silver nanoparticles (AgNPs) its affinity to virus and virucidal activity against herpes simplex 2 (HSV-2). We selected four different ligands, which potentially exhibit HSV-2 used them for functionalization AgNPs: i) sodium citrate: ii) tannic acid; iii) 1-mercaptoundecane-1-sulfonate (MUS); iv) poly(ethylene glycol) (PEG). The antiviral was performed by in vitro Vero cell culture. Anti- inflammatory measurement NF-κB activity. potential functional NPs vivo tested with model genital infection. Cryo- transmission electron microscopy (cryo-TEM) directly visualize interactions or lack assess their surface. It found that chemistry plays a key role modulation interaction virus. Two ligands (sodium citrate PEG) were inert show no AgNPs functionalized heparan sulfate-mimic (MUS) showed high surface, appearance these resulted deactivation about 50%. case acid, assessment is difficult be resolved, mainly because TA-AgNPs very strong effect (~100%) immediately after contact those structure being destroyed. obtained results indicate does not provide effectiveness. most effective revealed

Language: Английский

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Mechanistic Insights into Targeting SARS-CoV-2 Papain-like Protease in the Evolution and Management of COVID-19

BioChem, Journal Year: 2024, Volume and Issue: 4(3), P. 268 - 299

Published: Sept. 23, 2024

The COVID-19 pandemic, instigated by the emergence of novel coronavirus, SARS-CoV-2, created an incomparable global health crisis. Due to its highly virulent nature, identifying potential therapeutic agents against this lethal virus is crucial. PLpro a key protein involved in viral polyprotein processing and immune system evasion, making it prime target for development antiviral drugs combat COVID-19. To expedite search candidates, review delved into computational studies. Recent investigations have harnessed methods identify promising inhibitors targeting PLpro, aiming suppress activity. Molecular docking techniques were employed researchers explore binding sites within catalytic region PLpro. elucidates functional structural properties SARS-CoV-2 underscoring significance pathogenicity replication. Through comprehensive all-atom molecular dynamics (MD) simulations, stability drug–PLpro complexes was assessed, providing dynamic insights their interactions. By evaluating energy estimates from MD stable with identified. This offers overview drug/lead candidates discovered thus far using diverse silico methodologies, encompassing drug repurposing, structure-based, ligand-based virtual screenings. Additionally, identified are listed based on chemical structures meticulously examined according various parameters, such as estimated free (ΔG), types intermolecular interactions, PLpro–ligand complexes, determined outcomes simulations. Underscoring pivotal role battle COVID-19, establishes robust foundation integrating modeling, insights. continual imperative improvement existing exploring compounds remains paramount efforts evolution management hinge symbiotic relationship between experimental validation, interdisciplinary synergy crucial endeavor.

Language: Английский

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Recent studies on protein kinase signaling inhibitors based on thiazoles: review to date

RSC Advances, Journal Year: 2024, Volume and Issue: 14(50), P. 36989 - 37018

Published: Jan. 1, 2024

Due to the important role of protein kinases in phosphorylation within vital cellular processes, their abnormal function, especially cancer situations, has underscored importance therapy.

Language: Английский

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Synthesis and Molecular Docking Analysis of New Thiazo-isoindolinedione Hybrids as Potential Inhibitors of the SARS-CoV-2 Main Protease

Oriental Journal Of Chemistry, Journal Year: 2023, Volume and Issue: 39(4), P. 913 - 918

Published: Aug. 30, 2023

Herein, we report the synthesis of novel thiazo-isoindolinedione derivatives in excellent yields (up to 92%) from reaction thiazolidinedione and isoindoline-dione. The structures compounds were elucidated by 1H-, 13C-NMR, MS analyses. Furthermore, molecular docking analysis was performed study potential inhibition SARS-CoV-2 main protease (Mpro) new thiazo-isoindolinediones. present revealed that thiazo-isoindolinediones could inhibit Mpro represent a promising platform for experimental development antiviral drugs based on scaffolds.

Language: Английский

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