Development of Membrane-Targeting Osthole Derivatives Containing Pyridinium Quaternary Ammonium Moieties with Potent Anti-Methicillin-Resistant Staphylococcus aureus Properties

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-acquired infections, necessitating the development novel antibacterials. Here, we designed synthesized 30 osthole derivatives with pyridinium quaternary ammonium moieties. In vitro bioassay showed that compounds 8u 8ac exhibited potent antibacterial activity against S. ATCC 29213 ten clinical MRSA isolates (MIC = 0.5-1 μg/mL), low hemolytic activity, rapid bactericidal effects, minimal resistance induction. MRSA-infected mouse models skin abscesses sepsis, also displayed excellent effects safety, which were comparable to vancomycin. Mechanistic studies revealed selectively target bacterial membranes via binding phosphatidylglycerol (PG), increasing intracellular reactive oxygen species (ROS), inducing content leakage, ultimately causing death. These findings suggest as promising lead candidates for anti-MRSA drug development.

Language: Английский

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Oxazole and Isoxazole-containing Pharmaceuticals: Targets, Pharmacological Activities, and Their SAR Studies

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Oxazole, a five-membered aromatic heterocycle featuring nitrogen and an oxygen atom separated by carbon atom, its isomer isoxazole, with directly attached atoms, have been pivotal in medicinal chemistry. Over the past few decades, U.S. Food Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis Oxaprozin. Due to their unique physicochemical properties, often exhibit superior pharmacokinetic profiles pharmacological effects compared those similar heterocycles. This review provides comprehensive overview of all FDA-approved oxazole isoxazole nuclei, focusing on activities structure-activity relationships.

Language: Английский

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Assembly of thioether analogs from 2‐mercaptobenzoxazole‐fused honokiol and heterocyclic scaffolds and evaluation of their agrochemical potential

Pest Management Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Abstract BACKGROUND Persistent and excessive application of conventional synthetic pesticides has triggered a series environmental agricultural product safety risks in recent decades. Natural products are considered to provide considerable sources for the innovation novel ecofriendly agrochemicals with high efficacy. RESULTS In this work, structural splicing strategy was used prepare 37 honokiol‐derived thioether analogs bearing different heterocyclic scaffolds their pesticidal activities were assessed. Bioassay results showed that most target compounds have growth inhibitory activity against Mythimna separata . Notably, I1 I2 prominent M. 50% lethal concentration (LC 50 ) values 0.32 0.38 mg mL −1 , respectively, which superior precursor honokiol = 1.46 commercial insecticide toosendanin 0.63 ). Compounds E2 G9 demonstrated pronounced ovicidal eggs Plutella xylostella LC 6.34 7.49 μg compared value 46.96 Furthermore, seven E4 E6 E7 E8 G3 H5 I5 excellent larvicidal P. significantly outperforming positive control rotenone. Preliminary analysis structure–activity relationships reveals moieties introduced indeed beneficial insecticidal potential these compounds. CONCLUSION The remarkable potency position honokiol‐based reported herein as promising candidate leads further development pest management. © 2025 Society Chemical Industry.

Language: Английский

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Investigating the Antibacterial Efficiency and Mechanism of Indole- and Naphthalimide-Mediated Benzimidazoles: Membrane Damage, Metabolic Inactivation, and Oxidative Stress against Bacillus subtilis

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Resistance by bacteria to available antibiotics is a threat human health, which demands the development of new antibacterial agents. Considering prevailing conditions, we have developed series naphthalimide/indole benzimidazoles with diverse amines and aryl rings avoid molecular framework conventional drug molecules overcome cross-resistance issue. Most synthesized compounds, especially electron-withdrawing halide substituents, show broad-spectrum activity against both Gram-positive Gram-negative bacterial strains. Preliminary studies indicate that compounds IB-14 NB-8 display excellent Bacillus subtilis, exceeding performance marketed amoxicillin. In addition rapid bactericidal effect, significantly inhibit formation biofilm, lowering resistance. Moreover, exhibit fast-bactericidal properties, thus shortening time treatment also resisting emergence resistance up 20 passages. Further, biofunctional evaluation reveals effectively disrupt membrane, causing leakage cytoplasmic contents loss in metabolic activity. Both efficiently induce reactive oxygen species (ROS), leading oxidation GSH GSSG, decreasing cell, oxidative damage cells. DNA bind form DNA-IB-14/NB-8 complexes replication protein. The significant binding affinity HSA suggests easy transport candidates target site through carrier These findings suggest multitargeting potential as agents provide possibility global issue multidrug toward antibiotics.

Language: Английский

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Synthesis and anti-MRSA activity of quaternized small molecule antimicrobial peptide mimics based on norharmane

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 290, P. 117518 - 117518

Published: March 14, 2025

Language: Английский

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From Natural Products to Small Molecules: Recent Advancements in Anti-MRSA Therapeutics

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(4), P. 542 - 551

Published: March 14, 2025

The urgent need for unique small molecules to treat increasing resistance in gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus, has motivated several creative research endeavors over the past decade. Recent advances have been inspired by natural products such as pleuromutilin, discovered high-throughput screens, or repurposed approved drugs like sorafenib. This microperspective spotlights bioactive compounds, ranging from molecule scaffolds, that reported recent literature, highlighting their mechanisms of action, structure-activity relationships, and future potential.

Language: Английский

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Identification of hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of potential antibacterial agents

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130258 - 130258

Published: April 1, 2025

Language: Английский

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Synthesis of Novel Chromene Derivatives Bearing Hydrazide/Thiazol/Oxazol/Oxime Moieties as Potential Antifungal Agents

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Four series of novel hydrazide/thiazol/oxazol/oxime ester hybrids chromene derivatives were designed and synthesized to explore natural-product-based fungicide candidates. Preliminary antifungal activity assay results demonstrated that hydrazide-chromene thiazol-chromene exhibited excellent broad-spectrum inhibitory against ten phytopathogenic fungi. Among them, six compounds 4b, 4c, 4d, 4e, 4h, 4l displayed the most remarkable effects. Notably, 4e showed comparable protective curative effects with chlorothalonil potatoes cherry tomatoes infected by Fusarium solani Botrytis cinerea, respectively. Meanwhile, compound also exerted potential rice pepper leaves Pyricularia oryzae Phytophthora capsici, Additionally, a preliminary mechanism study revealed could significantly inhibit germination spores promote increased mycelium permeability content leakage disrupting fungal membrane structure. The in vitro cytotoxicity indicated almost all possessed relatively low cytotoxicity. These findings provide foundation for application chromene-based as

Language: Английский

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In vitro and in vivo evaluation of novel ursolic acid derivatives as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 154, P. 107986 - 107986

Published: Nov. 22, 2024

Language: Английский

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