article · RSC Advances
Researchers have synthesised a novel series of chemical compounds combining quinazolin-2,4-dione cores with acylthiourea linkages and five-membered nitrogen heterocycles, specifically pyrazole and oxazole moieties. These molecules were designed as potential antibacterial drug candidates operating through the inhibition of the bacterial DNA gyrase enzyme. The chemical structures were synthesised via multicomponent and Knoevenagel reactions, yielding high purity compounds that were fully characterized using spectroscopic methods. Biological evaluation assessed the minimum inhibitory concentration against two Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus. Among the tested series, compound 3c demonstrated the strongest antibacterial potency across all tested pathogenic strains at low concentrations, outperforming the standard antibiotic Ciprofloxacin. Molecular docking studies supported these findings by demonstrating favourable binding interactions with the target DNA gyrase enzyme.
Bacterial infections continue to present significant treatment challenges due to the ongoing need for effective antimicrobial therapies. By identifying chemical structures that successfully inhibit DNA gyrase and surpass the potency of conventional antibiotics like Ciprofloxacin in laboratory tests, this research provides new lead molecules that could contribute to the development of alternative antibacterial treatments.
This research could eventually enable the development of new antibacterial medications for use by pharmaceutical developers and healthcare providers targeting resistant bacterial strains. Based strictly on the provided laboratory synthesis, in vitro testing, and molecular docking studies, the technology represents very early-stage drug discovery. Substantial further work, including in vivo efficacy testing, toxicology assessments, and preclinical trials, would be required before commercial application is possible.
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This article contributes to the search for new therapeutic agents for treatment of diseases caused by bacterial pathogens. In this study, a new series of compounds incorporating numerous bioactive moieties such as quinazolin-2,4-dione, acylthiourea linkage, and/or five membered nitrogen heterocycles (pyrazole and oxazole) 2-5a-c was described to identify new antibacterial drug candidates <i>via</i> inhibition of DNA gyrase enzyme. The precursor <i>N</i>-[<i>N</i>'-(2-cyano-acetyl)-hydrazinocarbothioyl]-4-(2,4-dioxo-1,4-dihydro-2<i>H</i>-quinazolin-3-yl)-benzamide 2 was prepared by treatment of compound 1 with ammonium thiocyanate and cyanoacetic acid hydrazide through multicomponent reaction (MCR). In addition, compounds 3a-d and 4a-b were synthesized by treatment of 2 with aromatic aldehydes and/or ketones through Knoevenagel reaction, affording high purity products in satisfactory yields. Moreover, new heterocyclic moieties such as pyrazole and/or oxazole attached to quinazolin-2,4-dione core 5a-c were synthesized by treatment of 3c with different nucleophilic reagents like hydrazine, phenyl hydrazine and hydroxyl amine, respectively. Subsequently, the obtained products were structurally characterized by IR, <sup>1</sup>H-, <sup>13</sup>C-NMR, and MS analyses. The minimum inhibitory concentration (MIC) and antibacterial potency of all compounds were estimated against two G-ve (<i>E. coli</i> and <i>P. aeruginosa</i>), and two G+ve bacteria (<i>B. subtilis</i> and <i>S. aureus</i>). Encouragingly, compound 3c demonstrated the best antibacterial activity against all the strains of the tested pathogenic bacteria at low concentrations compared with the standard drug, Ciprofloxacin. Electron withdrawing groups such as -NO<sub>2</sub> and -Cl enhance the antibacterial activity. Next, a molecular docking study between the synthesized derivatives and the target enzyme, DNA gyrase enzyme (PDB: 2xct) was undertaken to investigate intermolecular interactions between the compounds and target enzyme.
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DOI: 10.1039/d4ra02960g
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