Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India.
Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Sector 10, Janakipuram Extension, Lucknow, 226031, Uttar Pradesh, India.
Eur J Med Chem. 2019 Aug 1;175:287-308. doi: 10.1016/j.ejmech.2019.04.067. Epub 2019 Apr 28.
Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 μg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC = >5 μg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4'c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 μg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC = 12.5->100 μg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.
金黄色葡萄球菌和结核分枝杆菌是导致全球医疗机构严重获得性和社区获得性感染的主要病原体。几十年来，这些病原体对抗生素的耐药性不断增强，显著影响了发病率和死亡率。因此，这些难以治疗的病原体是国际医疗机构强制要求积极识别和开发新的抗菌药物以进行化学治疗干预的最具威胁性的微生物病原体之一。在我们目前的工作中，设计、合成了一系列新的喹唑啉-4(3H)-酮衍生物，并评估了它们对 ESKAP 病原体和致病性分枝杆菌的抗菌活性。实验结果表明，4'c、4'e、4'f 和 4'h 对金黄色葡萄球菌具有选择性和强效的抑制活性，MIC 值范围为 0.03-0.25μg/mL。此外，化合物 4'c 和 4'e 对 Vero 细胞（CC>5μg/mL）表现出良性，并且显示出有希望的选择性指数（SI）>167 和>83.4。此外，4'c 和 4'e 对包括 VRSA 在内的多种耐药性金黄色葡萄球菌菌株具有等效的 MIC，对金黄色葡萄球菌具有浓度依赖性杀菌活性，并与 FDA 批准的药物协同作用。此外，化合物 4'c 在减少生物膜方面表现出更强的活性，并在 10X MIC 时表现出约 2 小时的 PAE，与左氧氟沙星和万古霉素相当。在小鼠中性粒细胞大腿感染模型中的 4'c 的体内疗效表明，4'c 引起的 cfu 减少与万古霉素相似。令人欣慰的是，化合物 4d、4e、9a、9b、14a、4'e 和 4'f 也表现出抗分枝杆菌活性，MIC 值在 2-16μg/mL 范围内。此外，这些化合物对 Vero 细胞的毒性较小（CC=12.5->100μg/mL），因此显示出良好的选择性指数。这里获得的有趣结果表明，这些新的喹唑啉-4(3H)-酮衍生物有潜力作为治疗 MDR-葡萄球菌和分枝杆菌感染的有前途的抗菌药物。
