Azoalkyl ether imidazo[2,1-b]benzothiazoles as potentially antimicrobial agents with novel structural skeleton

• Published in: Bioorganic & medicinal chemistry letters 2018-08, Vol.28 (14), p.2426-2431
• Main Authors: Maddili, Swetha Kameswari, Li, Zhen-Zhen, Kannekanti, Vijaya Kumar, Bheemanaboina, Rammohan R. Yadav, Tuniki, Balaraju, Tangadanchu, Vijai Kumar Reddy, Zhou, Cheng-He
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Dose-Response Relationship, Drug; Fungi - drug effects; Fungi - growth & development; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - growth & development; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - growth & development; Imidazo[2,1-b]benzothiazole; Microbial Sensitivity Tests; Molecular modeling; Molecular Structure; MRSA DNA interaction; Quantum Theory; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.06.016

[Display omitted] •Novel azoalkyl ether imidazo[2,1-b]benzothiazole analogues were prepared.•Compounds 5a is active against MRSA stains than Chloromycin and Norfloxacin.•Highly active compound 5a show DNA interaction via intercalation mode.•MRSA showed no developed resistance towards Compound 5a. A series of new azoalkyl ether imidazo[2,1-b]benzothiazoles were developed via a convenient synthetic procedure. The antimicrobial assays showed that a good number of the prepared derivatives exhibited significant inhibitory properties against most of the tested strains. Especially 2-methyl-5-nitroimidazole derivative 5a presented superior inhibit activity against MRSA and B. typhi with MIC = 4 μg/mL and MIC = 1 μg/mL, respectively. The highly active compound 5a showed low toxicity against mammalian cells without obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy. Molecular docking study exposed that the active molecule 5a could interact with the active site of S. aureus gyrase through hydrogen bond. Quantum chemical studies were also performed to explain the high antibacterial activity. Further investigation revealed that compound 5a could significantly associate with gyrase–DNA complex by mean of hydrogen bonds and could efficiently intercalate into MRSA DNA to form 5a–DNA supramolecular complex, which impart potent bioactivity.