Barbour Patrick M, Wang Wei, Chang Le, Pickard Kasey L, Rais Rana, Slusher Barbara S, Wang Xiang
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Department of Neurology and Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Adv Synth Catal. 2016 Apr 28;358(9):1482-1490. doi: 10.1002/adsc.201501101. Epub 2016 Mar 3.
Antibiotic resistance is a worldwide public health threat that needs to be addressed by improved antibiotic stewardship and continuing development of new chemical entities to treat resistant bacterial infections. Compounds that work alongside known antibiotics as combination therapies offer an efficient and sustainable approach to counteract antibiotic resistance in bacteria. Guided by property-based analysis, a series of aza-tricyclic indolines (ATIs) were synthesized to optimize their physiochemical properties as novel combination therapies with β-lactams to treat methicillin-resistant (MRSA) infections. A novel and highly efficient gold-catalyzed tandem cyclization was developed to facilitate the synthesis of these ATIs. One guanidine-containing ATI was discovered to possess both improved anti-MRSA activity and lower mammalian toxicity both in vitro and in vivo. In addition, it also showed significantly enhanced aqueous solubility and metabolic stability. These results indicated that the ATIs are a novel class of anti-MRSA agents suitable for further evaluations as adjuvant therapy in animal model studies.
抗生素耐药性是一个全球性的公共卫生威胁，需要通过改善抗生素管理以及持续开发新的化学实体来治疗耐药细菌感染加以应对。与已知抗生素联合使用的化合物作为联合疗法，为对抗细菌中的抗生素耐药性提供了一种有效且可持续的方法。在基于性质的分析指导下，合成了一系列氮杂三环吲哚啉（ATI），以优化其物理化学性质，作为与β-内酰胺类药物联合治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染的新型疗法。开发了一种新颖且高效的金催化串联环化反应，以促进这些ATI的合成。发现一种含胍的ATI在体外和体内均具有改善的抗MRSA活性和较低的哺乳动物毒性。此外，它还表现出显著增强的水溶性和代谢稳定性。这些结果表明，ATI是一类新型抗MRSA药物，适合在动物模型研究中作为辅助治疗进行进一步评估。
