We designed, synthesized, and tested twenty-six novel tetrahydroisoquinoline carbohydrazide compounds for their anti-mycobacterial activity. Utilizing mass spectrometry, ¹H NMR, ¹³C NMR, and elemental analysis, all the synthesized derivative structures were confirmed. The final analogs were tested for their ability to inhibit Mycobacterium tuberculosis (Mtb). The Mtb inhibitory activity outcomes varied from 0.78 to 25 μg mL⁻¹. Among all the investigated analogues, compounds NFT-12, NFT-19, and NFT-20 exhibited substantial activity with a MIC of 0.78 μg mL⁻¹ against Mtb H37Rv. Furthermore, the NFT-11 compound showed excellent activity with a MIC of 1.56 μg mL⁻¹. The majority of the compounds showed very good activity compared to the standard drug rifampicin (MIC 3.12 μg mL⁻¹). The most active compounds, NFT-12, NFT-19, and NFT-20, demonstrated selectivity over the normal human embryonic kidney cell line (HEK293T) with a selectivity index of >40. To determine whether the designed compounds exhibit synergistic effects or not, drug–inhibitor combination studies were carried out for the most active compounds using the standard drugs isoniazid, rifampicin, ciprofloxacin, and streptomycin. The improvement in pharmacological activities (x/y coefficients) demonstrates the effectiveness of the compounds NFT-12, NFT-19, and NFT-20 with isoniazid. The expected binding site of the test ligand at the active site of the chosen target proteins was determined using molecular docking studies. The most active compounds NFT-12, NFT-19, and NFT-20 were used in the docking experiments to determine the binding pattern at the active site with the Mycobacterium tuberculosis InhA (PDB ID: 4OHU, 1.60 Å).

中文翻译：

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基于四氢异喹啉的 5-硝基-2-糠酸衍生物：一种有前景的抗结核药物新方法

我们设计、合成并测试了二十六种新型四氢异喹啉碳酰肼化合物的抗分枝杆菌活性。利用质谱、¹ H NMR、¹³ C NMR和元素分析，确认了所有合成的衍生物结构。测试了最终类似物抑制结核分枝杆菌( Mtb )的能力。Mtb抑制活性结果在 0.78 至 25 μg mL ^-1之间变化。在所有研究的类似物中，化合物NFT-12、NFT -19和NFT-20表现出显着的活性，其 MIC 为 0.78 μg mL ^-1山地车H37Rv。此外，NFT-11化合物显示出优异的活性，MIC为1.56 μg mL ^-1。^{与标准药物利福平（MIC 3.12 μg mL -1}）相比，大多数化合物表现出非常好的活性。最活跃的化合物NFT-12、NFT-19和NFT-20表现出对正常人胚胎肾细胞系 (HEK293T) 的选择性，选择性指数 > 40。为了确定设计的化合物是否表现出协同作用，使用标准药物异烟肼、利福平、环丙沙星和链霉素对最具活性的化合物进行了药物-抑制剂组合研究。药理活性的改善（x / y系数）证明了化合物NFT-12、NFT-19和NFT-20与异烟肼的有效性。使用分子对接研究确定测试配体在所选靶蛋白活性位点的预期结合位点。最活跃的化合物NFT-12、NFT-19和NFT-20用于对接实验，以确定活性位点与结核分枝杆菌InhA （PDB ID：4OHU，1.60 Å）的结合模式。