Synthesis, antimicrobial activity and molecular modeling study of 3-(5-amino-(2H)-1,2,4-triazol-3-yl]-naphthyridinones as potential DNA-gyrase inhibitors

Mohamed, Nourhan; Sheha, Mahmoud; Hassan, Hoda Y.; Abdel-Hafez, Lina Jamil M; Omar, Farghaly A.

doi:10.1016/j.bioorg.2018.08.031

Cited by 26 publications

(6 citation statements)

References 36 publications

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“…Based on the reported SAR of fluoroquinolones , and on our work, , we set out to design and synthesize novel N 4-substituted piperazinyl derivatives of norfloxacin in an attempt to improve its potency and possibly enable new target interactions. Guided by a primary molecular docking study, a broad range of diverse aliphatic, cyclic, aromatic, and heterocyclic substituents were selected, including aliphatic amines, anilines, and nitrogen-containing heterocycles such as aminothiazoles, isatin, quinazolinones, imidazoles, triazoles, oxadiazoles, benzohydrazides, and isoniazid, which were added to norfloxacin using N -acetyl, thioacetyl, or methylene linkers (Figure ).…”

Section: Introductionmentioning

confidence: 99%

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

Kamal El-sagheir,

Abdelmesseh Nekhala,

Abd El-Gaber

et al. 2023

ACS Bio Med Chem Au

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Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gramnegative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.

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Section: Introductionmentioning

confidence: 99%

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

Kamal El-sagheir,

Abdelmesseh Nekhala,

Abd El-Gaber

et al. 2023

ACS Bio Med Chem Au

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“…Despite the presence of the 1,2,4-triazole nucleus in the structure of many biologically active compounds, broadspectrum antibacterial effects from 1,2,4-triazole derivatives were observed in cases linked to antibiotics such as clinafloxacin, nalidixic acid, ofloxacin, ciprofloxacin and norfloxacin. [31][32][33][34][35]…”

Section: Antibacterial Assaymentioning

confidence: 99%

One‐Pot Synthesis of 3‐Amino‐1,2,4‐triazoles Using Choline Chloride‐Urea and Their Antibacterial Activities

2022

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In this study, a new one‐pot method was proposed for the synthesis of novel and known 3‐amino‐1,2,4‐triazole derivatives in choline chloride/urea (1 : 2) as a biodegradable, nontoxic, biorenewable and inexpensive solvent and reagent. It efficiently catalyzed the reaction between alkyl/aryl hydrazides with urea. Some of the advantages of the proposed method are: eco‐friendly and low‐cost procedure, easy work‐up and purification, good to excellent product yields and acceptable reaction times. This method can be a model for Pellizzari‐type reactions. Antimicrobial activity of the synthesized 1,2,4‐triazoles were evaluated against five Gram‐positive and three Gram‐negative pathogenic bacteria via Kirby‐Bauer disk diffusion method. Triazoles containing 3‐bromophenyl and 4‐(tert‐butyl)phenyl substituents were the most effective antibacterial agents against all tested bacterial strains.

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“…Antimicrobial activity of 1,2,4-triazole-naphthyridinone hybrids 35 and 36 as structural surrogates of nalidixic acid ( Fig. 6 ) against resistant strains of Gram-positive, Gram-negative and Mycobacterium phlei indicated that hybrids 35a , 35f , 35g , 36a and 36d (MIC: 3.68–5.30 μM/mL) showed remarkable selectivity against B. subtilis, which was resistant to nalidixic acid [ 55 ]. Further study revealed that the compounds 35c and 36d (IC 50 : 3.67 and 3.21 μg/mL, respectively) elicited more potent inhibitory activity against E. coli DNA gyrase.…”

Section: Biological Activities Of 124-triazole Derivativesmentioning

confidence: 99%

An insight on medicinal attributes of 1,2,4-triazoles

Aggarwal

Sumran²

2020

European Journal of Medicinal Chemistry

199

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The present review aims to summarize the pharmacological profile of 1,2,4-triazole, one of the emerging privileged scaffold, as antifungal, antibacterial, anticancer, anticonvulsant, antituberculosis, antiviral, antiparasitic, analgesic and anti-inflammatory agents, etc. along with structure-activity relationship. The comprehensive compilation of work carried out in the last decade on 1,2,4-triazole nucleus will provide inevitable scope for researchers for the advancement of novel potential drug candidates having better efficacy and selectivity.

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Synthesis, antimicrobial activity and molecular modeling study of 3-(5-amino-(2H)-1,2,4-triazol-3-yl]-naphthyridinones as potential DNA-gyrase inhibitors

Cited by 26 publications

References 36 publications

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

One‐Pot Synthesis of 3‐Amino‐1,2,4‐triazoles Using Choline Chloride‐Urea and Their Antibacterial Activities

An insight on medicinal attributes of 1,2,4-triazoles

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