Novel Scaffolds Based on Bis-thiazole Connected to Quinoxaline or Thienothiophene through 2-Phenoxy-N-arylacetamide Groups as New Hybrid Molecules: Synthesis, Antibacterial Activity, and Molecular Docking Investigations

Abstract

The resistance of microorganisms to antimicrobials has endangered the health of many people across the world. Overcoming the resistance problem will require the invention of molecules with a new mechanism of action so that no crossresistance with existing therapies occurs. Because of their powerful antibacterial activity against a wide spectrum of Gram-positive and Gram-negative bacterial strains, heterocyclic compounds are appealing candidates for medicinal chemists. In this regard, as unique hybrid compounds, we synthesized a novel family of bisthiazoles linked to quinoxaline or thienothiophene via the 2-phenoxy-Narylacetamide moiety. The target compounds were synthesized by reacting the relevant bis(α-haloketones) with the corresponding thiosemicarbazones in EtOH at reflux with a few drops of TEA. Under comparable reaction conditions, the isomeric bis(thiazoles) were synthesized by reacting the appropriate bis(thiosemicarbazone) with the respective α-haloketones. The structures of the novel compounds were confirmed using elements and spectral data. All of the synthesized compounds were tested for antibacterial activity in vitro. With an inhibitory zone width of 12 mm, compound 12a had the same activity as the reference medication tobramycin against Staphylococcus aureus. Compound 12b showed 20 mg/mL as a minimum inhibitory concentration (MIC) against Bacillus subtilis. Some of the synthesized compounds were tested via molecular docking against two bacterial proteins (dihydrofolate reductase and tyrosyl-tRNA synthetase).

Synthesis of Novel Diphenyl Ether-Based Bis-Heterocycles as Novel Hybrid Molecules via Michael and Other Cyclocondensation Reactions

“…Hybridization may lead to the development of anticancer drugs that are both safer and more potent than those now available on the market. , Furthermore, due to their extraordinary lipophilicity, hydrophobicity, ability to penetrate cell walls, and resistance to degradation, diaryl ether substructures are important in various medications and recently discovered agrochemicals. , They have been discovered to have a variety of bioactivities, including antiviral, anticancer, antibacterial, β-glucuronidase enzyme inhibitory action, radical scavenging, cytotoxicity, antitubercular, and antitubulin activity. − Bis-heterocyclic compounds are among the popular scaffolds frequently found in drugs and pharmaceutically relevant substances because combining different heterocycle systems produces novel hybrid molecules that may be more biologically active than their separate components. There have been several reports of the antibacterial, anticancer, antiallergic, and other disease-fighting effects of bis-heterocycles. , Encouraged by the findings above and as part of our ongoing research interest in the synthesis of heterocycles and their bis-heterocyclic analogues, − we present the design and synthesis of novel hybrid molecules composed of diphenyl ether linked to various heterocyclic systems. In this context, we recently investigated the Hantzsch reaction for the manufacture of bis-dihydropyridine and their corresponding fused derivatives based on diphenyl ether, and their antibacterial activity against various bacterial strains was evaluated .…”