Department of Chemistry, University of Kerala, Kariavattom, Trivandrum 695581, India.
Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sector 10, Janakipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India; AcSIR: Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Bioorg Chem. 2022 Nov;128:106046. doi: 10.1016/j.bioorg.2022.106046. Epub 2022 Jul 25.
Green and facile synthesis of 24 tryptanthrin-thiopyrano[2,3-b]indole hybrid molecules is described (i) by a thermal one-pot multi-component strategy, (ii) using ammonium acetate in solvent-free conditions at 100 °C and (iii) by electrochemical method at room temperature. The in vitro antibacterial activities of compounds were evaluated against bacterial pathogen panel including clinically relevant highly drug-resistant MRSA/VRSA isolates, which led to the identification of nitro-substituted hybrid molecule 4c as being the most potent molecule against S. aureus ATCC 29213 with a high selectivity index. Upon further analysis, 4c exhibited concentration dependent bactericidal activity with a long PAE (post-antibiotic effect) and synergized with linezolid against S. aureus. From the in vitro metabolic stability assay (using rat liver microsomes) it was found that 4c has half-life of >120 min. The co-crystallographic studies indicated that amino group in compound 4c is the potential binding site. From all the studies, it was clear that compound 4c exhibits all the hallmarks for positioning it as a novel anti-staphylococcal therapeutic option.
描述了一种绿色、简便的 24 个色胺并噻吩[2,3-b]吲哚杂合分子的合成方法（i）通过热一锅多组分策略，（ii）在 100°C 无溶剂条件下使用乙酸铵，（iii）通过电化学方法在室温下进行。评估了化合物对细菌病原体的体外抗菌活性，包括临床相关的高度耐药性 MRSA/VRSA 分离株，这导致鉴定出硝基取代的杂合分子 4c 对金黄色葡萄球菌 ATCC 29213 具有最高的效力，具有高选择性指数。进一步分析表明，4c 表现出浓度依赖性杀菌活性，具有较长的 PAE（抗生素后效应），并与利奈唑胺协同作用对抗金黄色葡萄球菌。从体外代谢稳定性测定（使用大鼠肝微粒体）中发现，4c 的半衰期>120 分钟。共晶研究表明，化合物 4c 中的氨基是潜在的结合位点。从所有研究中可以清楚地看出，化合物 4c 表现出所有特征，使其成为一种新型的抗葡萄球菌治疗选择。
