Multi-drug resistant tuberculosis (MDR-TB) represents a growing problem for global healthcare systems. In addition to 1.3 million deaths in 2018, the World Health Organisation reported 484,000 new cases of MDR-TB. Isoniazid is a key anti-TB drug that inhibits InhA, a crucial enzyme in the cell wall biosynthesis pathway and identical in Mycobacterium tuberculosis and M. bovis. Isoniazid is a pro-drug which requires activation by the enzyme KatG, mutations in KatG prevent activation and confer INH-resistance. ‘Direct inhibitors’ of InhA are attractive as they would circumvent the main clinically observed resistance mechanisms. A library of new 1,5-triazoles, designed to mimic the structures of both triclosan molecules uniquely bound to InhA have been synthesised. The inhibitory activity of these compounds was evaluated using isolated enzyme assays with 2 (5-chloro-2-(4-(5-(((4-(4-chloro-2-hydroxyphenoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) exhibiting an IC₅₀ of 5.6 µM. Whole-cell evaluation was also performed, with 11 (5-chloro-2-(4-(5-(((4-(cyclopropylmethoxy)benzyl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenoxy)phenol) showing the greatest potency, with an MIC₉₉ of 12.9 µM against M. bovis.

耐多药结核病（MDR-TB）代表了全球医疗保健系统日益严重的问题。除了2018年有130万人死亡外，世界卫生组织还报告了48.4万例耐多药结核病新病例。异烟肼是抑制InhA的关键抗结核药物，InhA是细胞壁生物合成途径中的关键酶，与结核分枝杆菌和牛分枝杆菌相同。异烟肼是一种前药，需要被KatG酶激活，KatG中的突变会阻止激活并赋予INH抗性。InhA的“直接抑制剂”具有吸引力，因为它们可以绕开临床上观察到的主要耐药机制。合成了新的1,5-三唑库，该库旨在模拟与InhA唯一结合的两个三氯生分子的结构。这些化合物的抑制活性使用2（5-氯-2-（4-（5-（（（（4-（4-氯-2-羟基苯氧基）苄基）苄基）氧基）甲基）-1H- 1,2,3-三唑-1（基）苯氧基）苯酚）的IC ₅₀为5.6 µM。还进行了全细胞评估，其中11（5-氯-2-（4-（5-（（（（4-（环丙基甲氧基）苄基）氧基）甲基）-1H-1,2,3-三唑-1-基）苯氧基）苯酚显示出最大的效价，对牛分枝杆菌的MIC ₉₉为12.9 µM 。