Hu Yuan-Qiang, Zhang Shu, Zhao Feng, Gao Chuan, Feng Lian-Shun, Lv Zao-Sheng, Xu Zhi, Wu Xiang
School of Chemistry and Materials Science, Hubei Engineering University, Hubei, PR China.
Pony Testing International Group (Wuhan), Hubei, PR China.
Eur J Med Chem. 2017 Jun 16;133:255-267. doi: 10.1016/j.ejmech.2017.04.002. Epub 2017 Apr 3.
Tuberculosis (TB), which has been a scourge of humanity for thousands of years, is a worldwide pandemic disease caused mainly by Mycobacterium tuberculosis (MTB). The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug-resistant TB (TDR-TB) increase the challenges to eliminate TB worldwide. Isoniazid (INH), a critical frontline anti-TB drug, is one of the most effective drugs used to treatment of TB infection for more than 60 years. Unfortunately, bacterial strains resistant to INH are becoming common which mainly due to the long-term widely use even abuse. Therefore, there is an urgent need to develop novel anti-TB agents. Numerous efforts have been undertaken to develop new anti-TB agents, but no new drug has been introduced for more than 5 decades. It has been suggested that the incorporation of lipophilic moieties into the framework of INH can increase permeation of the drug into bacterial cells, thereby enhancing the anti-TB. Therefore, INH derivatives with greater lipophilicity are emerging as one of the most potential anti-TB agents. Indeed, the INH derivative LL-3858 is in initial stages of phase II clinical trial for the treatment of TB and may be approved to treat TB in the near future. This review aims to summarize the recent advances made towards the discovery anti-TB agents holding INH as a nucleus including INH hybrids and INH hydrazide-hydrazone derivatives.
结核病（TB）数千年来一直是人类的一大祸害，是一种主要由结核分枝杆菌（MTB）引起的全球性大流行病。耐药结核病（DR-TB）、耐多药结核病（MDR-TB）、广泛耐药结核病（XDR-TB）和完全耐药结核病（TDR-TB）的出现增加了全球消除结核病的挑战。异烟肼（INH）是一种关键的一线抗结核药物，是60多年来治疗结核感染最有效的药物之一。不幸的是，对INH耐药的菌株正变得越来越普遍，这主要是由于长期广泛使用甚至滥用。因此，迫切需要开发新型抗结核药物。人们已经做出了许多努力来开发新的抗结核药物，但50多年来没有推出新的药物。有人提出，将亲脂性部分引入INH的框架中可以增加药物进入细菌细胞的渗透性，从而增强抗结核作用。因此，具有更高亲脂性的INH衍生物正成为最具潜力的抗结核药物之一。事实上，INH衍生物LL-3858正处于治疗结核病的II期临床试验初始阶段，可能在不久的将来被批准用于治疗结核病。这篇综述旨在总结以INH为核心发现抗结核药物方面的最新进展，包括INH杂化物和INH酰肼-腙衍生物。
