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近年来细菌 II 型拓扑异构酶抑制剂的药物化学研究进展。

Recent advancements in the medicinal chemistry of bacterial type II topoisomerase inhibitors.

机构信息

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India.

出版信息

Bioorg Chem. 2020 Nov;104:104266. doi: 10.1016/j.bioorg.2020.104266. Epub 2020 Sep 3.

Abstract

Replication proteins are sought as a potential targets for antimicrobial agents. Despite their promising target characteristics, only topoisomerase II inhibitors targeting DNA gyrase and/or topoisomerase IV have reached clinical use. Topoisomerases are the enzymes that are essential for cellular functions and various biological activities. A wide range of natural and synthetic compounds have been identified as potential topoisomerase inhibitors but the resistance is most commonly found in these drugs. The emergence of FQ resistance has increased the need for the development of novel topoisomerase inhibitors with efficacy and high potency against FQ-resistant strains. Besides structural modifications of existing FQ scaffolds, novel non-quinolone topoisomerase II inhibitors, known as novel bacterial topoisomerase inhibitors, have been developed which showed remarkable inhibitory activity against DNA gyrase/topoisomerase IV or both with an improved spectrum of antibacterial potency including drug-resistant strains. This review aims to summarize various recent advancements in the medicinal chemistry of topoisomerase inhibitors with the following objectives: (1) To represent inclusive data on types of topoisomerases and various marketed topoisomerase inhibitors as drugs; (2) To discuss the recent advances in the medicinal chemistry of various topoisomerase inhibitors (DNA gyrase and topo IV) belonging to different structural classes as potential antibacterial agents; (3) To summarizes the structure activity relationship (SAR) including in silico and mechanistic studies to afford ideas and to provide focused direction for the development of new chemical entities which are effective against drug-resistant bacterial pathogens and biofilms.

摘要

复制蛋白被认为是抗菌药物的潜在靶标。尽管它们具有很有前途的靶标特征,但只有针对 DNA 拓扑异构酶 II 和/或拓扑异构酶 IV 的拓扑异构酶 II 抑制剂已达到临床应用。拓扑异构酶是细胞功能和各种生物活性所必需的酶。已经鉴定出广泛的天然和合成化合物作为潜在的拓扑异构酶抑制剂,但这些药物最常见的是耐药性。FQ 耐药性的出现增加了对具有针对 FQ 耐药菌株的疗效和高效力的新型拓扑异构酶抑制剂的开发需求。除了现有 FQ 支架的结构修饰外,还开发了新型非喹诺酮拓扑异构酶 II 抑制剂,称为新型细菌拓扑异构酶抑制剂,它们对 DNA 拓扑异构酶/拓扑异构酶 IV 或两者均显示出显著的抑制活性,并且具有改善的抗菌效力谱,包括耐药菌株。本综述旨在总结拓扑异构酶抑制剂的药物化学方面的最新进展,其目的如下:(1)代表有关拓扑异构酶类型和各种市售拓扑异构酶抑制剂作为药物的综合数据;(2)讨论属于不同结构类别的各种拓扑异构酶抑制剂(DNA 拓扑异构酶和拓扑异构酶 IV)的药物化学的最新进展,作为潜在的抗菌剂;(3)总结构效关系(SAR),包括计算和机制研究,以提供思路,并为开发针对耐药性细菌病原体和生物膜的新型化学实体提供重点指导。

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