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.
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