Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, 226031, Uttar Pradesh, India.
Eur J Med Chem. 2018 Sep 5;157:1056-1067. doi: 10.1016/j.ejmech.2018.08.070. Epub 2018 Aug 28.
Methicillin and vancomycin resistant Staphylococcus aureus infections are an emerging global health concern leading to increasing morbidity and mortality. Continuous increase in drug resistance has underlined the need for discovery and development of new antibacterial agents acting via novel mechanisms to overcome this pressing issue. In this context, a number of 1,2,3-triazole linked 4(3H)-quinazolinone derivatives were designed and synthesized as potent antibacterial agents. When evaluated against ESKAP pathogen panel, compounds 7a, 7b, 7c, 7e, 7f, 7g, 7h, 7i, 9a, 9c, 9d and 9e exhibited significantly selective inhibitory activities towards Staphylococcus aureus (MIC = 0.5-4 μg/mL). To understand and confirm the specificity of these compounds, the compounds 7a and 9a were tested against E. coli and A. baumannii in combination with sub-lethal concentrations of Polymyxin B nonapeptide (PMBN) and were found to be inactive. This clearly indicated that these compounds possess specific and potent activity towards S. aureus and are inactive against gram-negative pathogens. Encouragingly, the compounds were also found to be non toxic to Vero cells and displayed favourable selectivity index (SI = 40 to 80). Furthermore, 7a and 9a were found to possess potent inhibitory activity when tested against multidrug resistant S. aureus including strains resistant to vancomycin (MIC values 0.5-32 μg/mL), indicating that the compounds are able to escape current drug-resistance mechanisms. With the potent anti-bacterial activity exhibited the new series of 1,2,3-triazole linked 4(3H)-quinazolinones have emerged as promising candidates for treating multidrug resistant Staphylococcus aureus infections.
耐甲氧西林和万古霉素金黄色葡萄球菌感染是一个新兴的全球健康关注问题，导致发病率和死亡率不断上升。药物耐药性的持续增加强调了需要发现和开发新的抗菌药物，通过新的机制来克服这一紧迫问题。在这种情况下，设计并合成了一系列 1,2,3-三唑连接的 4(3H)-喹唑啉酮衍生物作为有效的抗菌剂。在评估对 ESKAP 病原体组时，化合物 7a、7b、7c、7e、7f、7g、7h、7i、9a、9c、9d 和 9e 对金黄色葡萄球菌表现出显著的选择性抑制活性（MIC = 0.5-4μg/mL）。为了理解和确认这些化合物的特异性，将化合物 7a 和 9a 与亚致死浓度的多粘菌素 B 九肽（PMBN）一起测试对大肠杆菌和鲍曼不动杆菌的抑制活性，发现它们没有活性。这清楚地表明，这些化合物对金黄色葡萄球菌具有特异性和强效活性，对革兰氏阴性病原体无活性。令人鼓舞的是，这些化合物对 Vero 细胞也没有毒性，显示出良好的选择性指数（SI = 40 到 80）。此外，在测试对包括耐万古霉素的金黄色葡萄球菌在内的多药耐药金黄色葡萄球菌时，化合物 7a 和 9a 被发现具有有效的抑制活性（MIC 值为 0.5-32μg/mL），这表明这些化合物能够逃避当前的耐药机制。具有强大的抗菌活性，新的 1,2,3-三唑连接的 4(3H)-喹唑啉酮系列已成为治疗多药耐药金黄色葡萄球菌感染的有前途的候选药物。
