Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
SAMRC Drug Discovery and Development Research Unit, University of Cape Town, Cape Town 7700, South Africa.
Bioorg Chem. 2020 Mar;96:103587. doi: 10.1016/j.bioorg.2020.103587. Epub 2020 Jan 16.
The emergence of drug-resistant tuberculosis (DR-TB) as well as the requirement for long, expensive and toxic drug regimens impede efforts to control and eliminate TB. Therefore, there's a need for effective and affordable anti-mycobacterial agents which can shorten the duration of therapy and are active against Mycobacterium tuberculosis (Mtb) in both active and latent phases. Nitrofurantoin (NFT) is a hypoxic agent with activity against a myriad of anaerobic pathogens and, like the first-line TB drug, rifampicin (RIF), kills non-replicating bacilli. However, the poor ability of NFT to cross host cell membranes and penetrate tissue means that it does not reach therapeutic concentrations. To improve TB efficacy of NFT, a series of NFT analogues was synthesized and evaluated in vitro for anti-mycobacterial activity against the laboratory strain, Mtb H37Rv, and for potential cytotoxicity using human embryonic kidney (HEK-293) and Chinese hamster ovarian (CHO) cells. The NFT analogues showed good safety profiles, enhanced anti-mycobacterial potency, improved lipophilicity, as well as reduced protein binding affinity. Analogue 9 which contains an eight carbon aliphatic chain was the most active, equipotent to isoniazid (INH), a major front-line agent, with MIC = 0.5 μM, 30-fold more potency than the parent drug, nitrofurantoin (MIC = 15 μM), and 100-fold more selective towards mycobacteria. Therefore, 9 was identified as a validated hit for further investigation in the urgent search for new, safe and affordable TB drugs.
耐多药结核病（DR-TB）的出现以及对长期、昂贵和有毒药物方案的需求，阻碍了控制和消除结核病的努力。因此，需要有效的、负担得起的抗分枝杆菌药物，这些药物可以缩短治疗时间，并且对活跃期和潜伏期的结核分枝杆菌（Mtb）均有效。硝呋太尔（NFT）是一种缺氧剂，对多种厌氧病原体具有活性，并且与一线结核病药物利福平（RIF）一样，能够杀死非复制菌。然而，NFT 穿过宿主细胞膜和穿透组织的能力很差，意味着它无法达到治疗浓度。为了提高 NFT 在结核病方面的疗效，合成了一系列 NFT 类似物，并在体外对实验室菌株 Mtb H37Rv 的抗分枝杆菌活性以及对人胚肾（HEK-293）和中国仓鼠卵巢（CHO）细胞的潜在细胞毒性进行了评估。NFT 类似物表现出良好的安全性、增强的抗分枝杆菌效力、改善的亲脂性以及降低的蛋白结合亲和力。含有 8 个碳原子脂肪链的类似物 9 是最活跃的，与异烟肼（INH）等主要一线药物等效，MIC = 0.5 μM，比母体药物硝呋太尔（MIC = 15 μM）的效力高 30 倍，对分枝杆菌的选择性高 100 倍。因此，9 被确定为进一步研究的有效命中物，以迫切寻找新的、安全和负担得起的结核病药物。
