4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis

Arnold, M.; Gerasyuto, Aleksey I.; Wang, Jiashi; Du, Wu; Gorske, Yi Jin Kim; Arasu, Tamil; Baird, John D.; Almstead, Neil G.; Narasimhan, Jana; Peddi, Srinivasa R.; Ginzburg, O. F.; Lue, Stanley W.; Hedrick, Jean; Sheedy, Josephine; Lagaud, Guy; Branstrom, Arthur; Weetall, Marla; Prasad, J. V. N. Vara; Karp, Gary M.

doi:10.1016/j.bmcl.2017.10.006

Cited by 8 publications

(11 citation statements)

References 16 publications

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“…Furthermore, 2-pyridones represent a unique class of pharmacophores that are represented in several antibiotics and therapeutic agents [33][34][35]. Additionally, 2-pyridones are a class of recently discovered potent antibacterial agents that are of interest due to their antibacterial potency against the bacterial type II DNA topoisomerases, which contain two homologous enzymes as topoisomerase IV and DNA gyrase [36]; also, 2-oxopyridine derivatives are isomeric with a 4-oxopyridine bioactive core that exist in the fluoroquinolone antibiotic class as ciprofloxacin, delafloxacin, and norfloxacin [37,38].…”

Section: Introductionmentioning

confidence: 99%

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

et al. 2021

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Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.

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Section: Introductionmentioning

confidence: 99%

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

et al. 2021

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“…Arnold et al . have synthesized novel pyridone derivatives (e) and observed potent antibacterial agent . Cyano containing pyridone (f) derivatives have been synthesized by novel route and found as potent antiproliferative agents (Fig.…”

Section: Introductionmentioning

confidence: 99%

An Efficient One‐Pot Synthesis of Highly Substituted Pyridone Derivatives and Their Antimicrobial and Antifungal Activity

Pandit¹,

Savant²,

Ladva³

2018

Journal of Heterocyclic Chem

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A series of carboxamide and cyano functionalized pyridone derivatives 4a-q have been synthesized via one-pot synthesis of various aldehydes 1a-q, acetoacetanilide 2, and cyanoacetamide 3. The reaction was simple and afforded pyridone derivatives in good yield, 89 to 93%. The novel pyridone derivatives were achieved by Hantzch one-pot synthesis. Moreover, the synthesized compounds were screened against Gram-positive and Gram-negative bacteria and fungi for their activity. Among them, compound 4c shows highest inhibition at 4.25 mm against Staphylococcus aureus and 3.75 mm against Escherichia coli Grampositive and Gram-negative bacteria, respectively.

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“… 29 Further, the basic nitrogen in 2d resulted in a >4-fold reduction in the MIC shift in the presence of HSA against E. coli WT compared to 2b . 15 …”

Section: Resultsmentioning

confidence: 99%

“…Compound 1b had modest in vitro antibacterial activity and demonstrated efficacy in a murine septicemia model. 15 Against an abbreviated panel of E. coli strains, the MIC 90 , defined as the lowest concentration inhibiting 90% of the isolates, was 8 μg/mL.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

et al. 2018

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There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5–1 μg/mL) and Acinetobacter baumannii (8–16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.

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4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis

Cited by 8 publications

References 16 publications

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors

An Efficient One‐Pot Synthesis of Highly Substituted Pyridone Derivatives and Their Antimicrobial and Antifungal Activity

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

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