School of Chemistry and Physics, College of Agriculture, Engineering and Science, University of KwaZulu Natal, Westville Campus, Durban 4000, South Africa.
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, School of Laboratory Medicine and Medical Sciences, College of Heath Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa.
Bioorg Chem. 2023 Dec;141:106904. doi: 10.1016/j.bioorg.2023.106904. Epub 2023 Oct 9.
New benzimidazole-1,2,3-triazole-quinoline hybrids and their intermediates, differing in substitutions at the C-2 and/or C6 positions of the benzimidazole ring, were successfully synthesized in 55---80 % yields, with the C6-substituted ones forming as inseparable tautomeric mixtures. The synthesized compounds were fully characterised by FT-IR, 1D- and 2D-NMR, and HRMS. In-depth NMR analysis and DFT molecular calculations showed that the tautomeric mixtures formed in a ratio of almost 1:1 ratio (cis and trans), except for 5 g, where the ratio is 1:2. In vitro antimycobacterial activity evaluation against the H37Rv strain of Mycobacterial tuberculosis was undertaken on all synthesized compounds, and a selected number were further screened for their cytotoxicity on TZM-bl cell lines. Hybrid compounds showed excellent MIC activities ranging from 1.07 to 8.66 μM and were all more efficacious than the first-line reference drug, ethambutol (MIC = 9.54 μM). In particular, hybrid compounds 5b (MIC = 1.54 μM, CC = 58.89 μM and % cell viability = 14.07), 5d (MIC = 2.08 μM, CC = 0.27 μM, and % cell viability = 149.50 %) and 5 g (MIC = 1.49 μM, CC = 4.62 μM and % cell viability = 44.03) were the most promising. Significantly, 5b and 5 g were over six times more efficacious than ethambutol but exhibited cytotoxicity towards TZM-bl cell-lines compared to 5d, which was over four times more active than ethambutol. The physical combination (mimicking combination therapy) of individual pharmacophoric components making up 5 g were less active, indicating the synergistic effect of hybridization. In addition, more than 60 % of all the synthesized hybrids showed better activity than their respective pharmacophoric components. In silico ADME studies of the hybrids revealed favourable physico-chemical properties, while molecular modeling studies suggested binding interactions with Val 61, Gly 62, Glu 65, Ala 66, and Phe 69 amino acid in a reported similar manner to bedaquiline, an approved quinoline-based anti-TB drug.
新型苯并咪唑-1,2,3-三唑-喹啉杂合体及其中间体成功合成，产率为 55-80%，苯并咪唑环的 C-2 和/或 C6 位置的取代基不同，其中 C6-取代物形成不可分离的互变异构混合物。合成的化合物通过傅里叶变换红外光谱（FT-IR）、1D 和 2D-NMR 以及高分辨率质谱（HRMS）进行了全面表征。深入的 NMR 分析和密度泛函理论（DFT）分子计算表明，除了 5g 之外，其余形成的互变异构混合物的比例几乎为 1:1（顺式和反式），5g 的比例为 1:2。对所有合成化合物进行了针对结核分枝杆菌 H37Rv 株的体外抗分枝杆菌活性评估，并进一步筛选了一些化合物对 TZM-bl 细胞系的细胞毒性。杂合体显示出优异的 MIC 活性，范围为 1.07 至 8.66 μM，均比一线参考药物乙胺丁醇（MIC=9.54 μM）更有效。特别是杂合体 5b（MIC=1.54 μM，CC=58.89 μM，细胞存活率%=14.07）、5d（MIC=2.08 μM，CC=0.27 μM，细胞存活率%=149.50）和 5g（MIC=1.49 μM，CC=4.62 μM，细胞存活率%=44.03）最有前途。值得注意的是，5b 和 5g 的功效比乙胺丁醇高 6 倍以上，但对 TZM-bl 细胞系的细胞毒性比 5d 高，5d 的功效比乙胺丁醇高 4 倍以上。组成 5g 的个别药效团成分的物理组合（模拟联合治疗）活性较低，表明杂交的协同作用。此外，超过 60%的合成杂合体比其各自的药效团成分表现出更好的活性。杂合体的体内 ADME 研究显示出良好的物理化学性质，而分子建模研究表明，它们以与已批准的喹啉类抗结核药物贝达喹啉类似的方式与 Val 61、Gly 62、Glu 65、Ala 66 和 Phe 69 氨基酸结合。
