Antimicrobial Activity of Substituted Benzopentathiepin-6-amines

• Published in: Journal of antibiotics Vol. 72; no. 8; pp. 590 - 599
• Main Authors: Khomenko, Tatyana M., Korchagina, Dina, Baev, Dmitry S., Vassiliev, Pavel M., Volcho, Konstantin P., Salakhutdinov, Nariman F.
• Format: Journal Article
• Language: English
• Published: LONDON Springer Nature 01.08.2019; Nature Publishing Group
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antimicrobial agents; Biotechnology & Applied Microbiology; Fungi - drug effects; Heterocyclic Compounds, Fused-Ring - chemical synthesis; Heterocyclic Compounds, Fused-Ring - pharmacology; Immunology; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Microbiology; Molecular Docking Simulation; Molecular Structure; Pathogens; Pharmacology & Pharmacy; Quantitative Structure-Activity Relationship; Science & Technology; Sulfides - chemical synthesis; Sulfides - pharmacology; IN-VITRO; DESIGN; DNA-LIGASE INHIBITORS; ANALOGS; NATURAL-PRODUCTS; DRUG DISCOVERY; BIOLOGICAL EVALUATION; 8-(TRIFLUOROMETHYL)-1,2,3,4,5-BENZOPENTATHIEPIN-6-AMINE; VARACIN
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-019-0191-y

A number of substituted benzopentathiepin-6-amines and their analogues without a polysulfur ring were synthesized and evaluated in vitro for antimicrobial activity against a panel of reference bacterial and fungal strains. Trifluoroacetamide 14 demonstrated high antibacterial activity against Staphylococcus aureus (MRSA strain) with a MIC of 4 mu g/mL, which was four-fold higher than the activity of a reference drug amoxicillin. This compound was also most active against the Candida albicans fungus (MIC of 1 mu g ml(-1)), whereas amide 17 containing a morpholine substituent was most active against the Cryptococcus neoformans fungus (MIC of 2 mu g ml(-1)). These compounds have no hemolytic activity and are low cytotoxic. Replacement of the pentathiepine ring with 1,3-dithiolan-2-one or 1,3-dithiolane moieties leads to loss of antimicrobial activity. Based on the QSAR analysis and molecular docking data, bacterial DNA ligase might be one of the targets for the antibacterial activity of substituted benzopentathiepin-6-amines against S. aureus.