Zhang Gui-Fu, Zhang Shu, Pan Baofeng, Liu Xiaofeng, Feng Lian-Shun
School of Nuclear Technology and Chemistry & Life Science, Hubei University of Science and Technology, Hubei, PR China.
Pony Testing International Group (Wuhan), Hubei, PR China.
Eur J Med Chem. 2018 Jan 1;143:710-723. doi: 10.1016/j.ejmech.2017.11.082. Epub 2017 Nov 29.
Gram-positive bacteria are responsible for a broad range of infectious diseases, and the emergency and wide spread of drug-resistant Gram-positive pathogens including MRSA and MRSE has caused great concern throughout the world. 4-Quinolones which are exemplified by fluoroquinolones are mainstays of chemotherapy against various bacterial infections including Gram-positive pathogen infections, and their value and role in the treatment of bacterial infections continues to expand. However, the resistance of Gram-positive organisms to 4-quinolones develops rapidly and spreads widely, making them more and more ineffective. To overcome the resistance and reduce the toxicity, numerous of 4-quinolone derivatives were synthesized and screened for their in vitro and in vivo activities against Gram-positive pathogens, and some of them exhibited excellent potency. This review aims to outlines the recent advances made towards the discovery of 4-quinolone-based derivatives as anti-Gram-positive pathogens agents and the critical aspects of design as well as the structure-activity relationship of these derivatives. The enriched SAR paves the way to the further rational development of 4-quinolones with a unique mechanism of action different from that of the currently used drugs to overcome the resistance, well-tolerated and low toxic profiles.
革兰氏阳性菌可引发多种传染病，耐甲氧西林金黄色葡萄球菌（MRSA）和耐甲氧西林表皮葡萄球菌（MRSE）等耐药革兰氏阳性病原体的出现和广泛传播已引起全球高度关注。以氟喹诺酮为代表的4-喹诺酮类药物是治疗包括革兰氏阳性病原体感染在内的各种细菌感染的主要化疗药物，其在细菌感染治疗中的价值和作用不断扩大。然而，革兰氏阳性菌对4-喹诺酮类药物的耐药性迅速发展并广泛传播，导致这些药物越来越无效。为了克服耐药性并降低毒性，人们合成并筛选了大量4-喹诺酮衍生物，以评估它们对革兰氏阳性病原体的体外和体内活性，其中一些表现出优异的效力。本综述旨在概述基于4-喹诺酮的衍生物作为抗革兰氏阳性病原体药物的最新研究进展、设计的关键方面以及这些衍生物的构效关系。丰富的构效关系为进一步合理开发4-喹诺酮类药物铺平了道路，这些药物具有不同于现有药物的独特作用机制，能够克服耐药性，且耐受性良好、毒性较低。
